Triazinones

ABSTRACT

Novel s-triazine compounds are prepared as derivatives of the corresponding amidinourea and amidinothiourea compounds by reacting with an activated form of an acid amide to give substituted s-triazinones and thiones respectively, of the formula ##STR1## The s-triazinones and thiones are useful derivatives in analyzing for the corresponding amidinourea or amidino thiourea precursors and also have useful pharmacological properties which make them suitable for a variety of medicinal purposes including use as antidiarrheal agents.

FIELD OF THE INVENTION

This invention pertains to a novel method for cyclizing amidinoureas andamidino thioureas, to novel heterocyclic compounds produced by themethod, and to a novel analytical method.

Amidinourea and amidinothiourea and their derivatives are known in theart and have been previously disclosed as having useful pharmacologicalproperties. Such compounds are disclosed for example in U.S. Pat. Nos.4,060,635 and 4,058,557 and in co-pending application Ser. No. 671,762now abandoned all of which are assigned to the assignee of the presentapplication.

In the development of pharmacologically active compounds for drug use inthe treatment of human disorders it is well recognized that extensivetesting is carried out to define among other things the mode of action,toxicity and ultimate fate of the drug which is administered to thepatient. In particular, the amidinoureas continue to be extensivelyinvestigated for a variety of pharmacodynamic effects. An important partof such investigations involves the analyses of samples of materialssuch as body tissue, blood serum, secretions and excretions to determinethe qualitative and quantitative presence of the drug in order toestablish the characteristics of the drug with respect to absorption,diffusion and transport, biotransformation by decomposition orconjunction and ultimate elimination from the body followingadministration to humans or animals including test animals. Gaschromatographic analysis has been found to be a useful tool fordetecting the presence of a drug in a sample containing a variety ofother materials. However, for gas chromatographic detection the drugmust be capable of being volatilized without degradation at thetemperature of the carrier gas and must be inert to both the carrier gasand the column packing material.

Gas chromatographic analysis of polar organic amides has proveddifficult owing to strong interaction between the functional groups andthe surface active sites in the stationary materials comprising thechromatographic column. These difficulties can frequently be overcome byfirst converting the organic amides to less active derivatives such asby forming an alkyl ester of the carboxyl group followed by acylation ofthe primary amino group. Primary amino groups have also been derivatizedby reacting with dimethyl-formamide dimethylacetal (DMF DMA) to form thedimethyl aminomethylene derivative. The same reagent has also been usedto esterify carboxyl groups. More recently DMF DMA has been used tosimultaneously derivatize carboxylic and amino groups by reacting withamino acids containing only primary amino and carboxyl groups; AnalyticLetters, 5(8), 519-529 1972.

Since the use of gas chromatographic techniques to analyze foramidinoureas directly proved difficult, derivatization of the functionalgroups utilizing DMF DMA as the derivatizing reagent was attempted. Theanalysis of amidinoureas and amidinothioureas by gas chromatographictechniques was found to be facilitated by such derivatization thoughunexpectedly the derivatives obtained proved to be a novel class ofs-triazinone and thione compounds, more particularly, 1,4-substituted1,2-dihydro-1,3,5-triazin-2-ones and 1,4-substituted-1,2-dihydro-1,3-5triazin-2-thiones.

DESCRIPTION OF THE PRIOR ART

As disclosed in co-pending application Ser. No. 671,762, the disclosureof which is hereby incorporated by reference the amidinoureas can existin various tautomeric or alternative structural forms. The same is truefor the amidino thioureas. Among the theoretical forms of theamidinoureas described in said co-pending application are structureshaving primary amino groups and therefore it might be theorized that thedimethyl amino methylene derivative of such amidinoureas could beprepared by reacting with DMF DMA. Repeated efforts to prepare thederivatives of numerous amidinoureas led instead to the preparation oftriazine compounds of novel structure which were nonetheless found to besuitable for gas chromatographic analysis to determine the qualitativeand quantitative presence of the corresponding amidinourea. In ananalogous way suitable triazine derivatives of the correspondingamidinothioureas are also prepared.

Substituted triazines are well known as are a variety of triazinones andthiones prepared by a number of synthetic routes, for example, asdescribed in U.S. Pat. No. 3,585,197. However, it does not appear thatprior disclosures taught that 1,4-disubstituted triazinones especiallythose having an aryl or aralkyl substituent, can be readily prepared innearly quantitative yield by cyclizing the corresponding amidinoureaswith a derivatizing agent in accordance with the present invention. Thepreparation of s-triazin-2-ones and s-triazin-2-thiones in accordancewith this technique provides a variety of novel triazine derivativeswhich are biologically active when administered to mammalian species toproduce useful pharmacotherapeutic effects. Accordingly, it is an objectof this invention to provide a novel process for the preparation oftriazines by cyclizing amidinoureas and amidinothioureas thereby toprovide derivatives which are useful inter alia as analytical tools todetermine the presence of the corresponding amidinoureas oramidinothioureas by gas chromotographic methods which would otherwisenot be possible.

Additionally, it is an object of this invention to provide a novel classof compounds possessing useful pharmacological properties which novelcompounds and their pharmaceutically acceptable salts can be used forthe treatment of a variety of physiological disorders, e.g., diarrheaand other gastrointestinal disorders.

SUMMARY

In accordance with the present invention, there is provided a novelclass of 1,4-substituted-1,2-dihydro-1,3,5-triazin-2-ones and thiones offormula I ##STR2## wherein: X is

oxygen or

sulfur;

R₁ is

aryl,

aralkyl,

5 or 6 membered heterocyclic groups or

5 or 6 membered heterocyclic groups attached to the triazine through alower alkylidene group;

R₂ is

hydrogen or

loweralkyl; and

R₃ and R₄ are each independently selected from the group consisting of

hydrogen,

hydroxyl,

acyl,

an aliphatic or substituted aliphatic group,

an aromatic group,

an aliphatic or aromatic ether group or a heterocyclic group;

or together R₃ and R₄ are alkylene or alkylene interrupted by 0 to 2hetero atoms which may be N, O or S so that R₃ and R₄ together with thenitrogen to which they are attached form a 3 to 7 membered ringcontaining 1 to 3 hetero atoms.

The cyclic derivative can be used to assay for the correspondingamidinourea or amidinothiourea by injecting a sample along with asuitable vaporizable carrier into a gas chromatograph. The compounds canalso be used for pharmacotherapeutics by administering to animals orhumans suitable dosage forms containing an effective amount for thetreatment of gastrointestinal irregularities such as diarrhea.

In one aspect this invention pertains to a novel class of triazineswhich are prepared as derivatives of amidinoureas or amidinothioureas toprovide a gas chromatographic method for detecting the presence of theamidinourea or amidinothiourea in a sample containing the amidinourea oramidinothiourea in admixture with unknown materials.

In another aspect this invention provides a novel analytical method toassay for amidinoureas and amidinothioureas in biological samples.

In yet another aspect, this invention provides a novel cyclizingreaction for the preparation of triazines and triazine derivatives.

In still another aspect, this invention provides compounds which areuseful in pharmacotherapeutics particularly as antidiarrheals or asantimotility or antisecretory agents or as antispasmodic agents.

Certain of the novel compounds also have effects on nerve tissueindicating use in the control of disorders involving abnormal nerveimpulse transmission.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

According to the novel compound aspect of this invention, there isprovided a new class of substituted triazines, more particularly a novelclass of s-triazinones and s-triazinthiones of the formula: ##STR3##wherein: X is

oxygen or

sulfur;

R₁ is

aryl,

aralkyl,

5 or 6 membered heterocyclic groups or

5 or 6 membered heterocyclic groups attached to the triazine through alower alkylidene group;

R₂ is

hydrogen or

loweralkyl; and

R₃ and R₄ are each independently selected from the group consisting of

hydrogen,

hydroxyl,

acyl,

an aliphatic or substituted aliphatic group,

an aromatic group,

an aliphatic or aromatic ether group, or

a 5 or 6 membered heterocyclic group; or

together R₃ and R₄ are alkylene or alkylene interrupted by 1 or 2 heteroatoms which may be N, O or S, so that R₃ and R₄ together with thenitrogen to which they are attached form a 3 to 7 membered ringcontaining 1 to 3 hetero atoms;

and their non-toxic pharmaceutically acceptable salts.

Depending upon the specific substitution, compounds of formula I abovemay be present in enolized or tautomeric forms. Certain of the compoundscan also be obtained as hydrates or in different polymorphic forms. Thestructures used herein to designate novel compounds are intended toinclude the compound shown along with its alternatives or transientstates. The nomenclature generally employed to identify the noveltriazine derivatives as disclosed herein is based upon the ringstructure shown in formula I with the triazine ring positions numberedcounterclockwise beginning with the nitrogen having the R₁ substitution.

s-triazinones and s-triazinthiones of this invention which form apreferred class of novel compounds, are those represented by the formulaI-a. ##STR4## wherein: X is

oxygen or

sulfur;

R₁ is

phenyl,

benzyl or

phenethyl;

or phenyl, benzyl or phenethyl in which one or more of the phenylhydrogens are substituted by

loweralkyl,

loweralkoxy,

halo,

haloloweralkyl,

amino,

nitro,

acyloxy,

acylamino,

hydroxy,

cyano,

carboxyl, or

loweralkylsulfonyl (especially 2'6'-disubstituted phenyl, benzyl orphenethyl);

pyridyl or substituted pyridyl;

R₂ is

hydrogen or

loweralkyl; and

R₃ and R₄ are each independently selected from the group consisting of

hydrogen,

hydroxyl,

loweralkanoyl,

loweralkyl,

loweralkenyl,

loweralkynyl,

loweralkoxy,

haloloweralkyl,

hydroxyloweralkyl,

loweralkoxyloweralkyl,

phenoxyloweralkyl,

diloweralkylamino,

loweralkyl, or

R₃ and R₄ together with the nitrogen to which they are attached form a 5or 6 membered nitrogen heterocycle containing 0 to 1 additional heteroatoms which may be

nitrogen,

oxygen or

sulfur;

and their non-toxic salts.

When R₁ is pyridyl in formula I-a above, the preferred groups are thosewherein the pyridyl nitrogen is adjacent to the ring carbon attached tothe triazinone ring, i.e. a 2-pyridyl and substituted pyridyls in whichone or both pyridyl ring carbons adjacent to the carbon attached to thetriazinone ring are substituted by loweralkyl, loweralkoxy, orhaloloweralkyl.

Where R₁ is substituted phenyl, benzyl or phenethyl, the preferredsubstituents on the phenyl moiety are the loweralkyl, halo, andloweralkoxyphenyl groups in the ortho positions. The substituents may bethe same or different.

A more specific group of preferred compounds according to this inventionare the s-triazinones of formula I-b. ##STR5## wherein: R₂ is

hydrogen or

loweralkyl;

R₃ and R₄ are each

hydrogen,

loweralkyl,

hydroxy,

loweralkoxy,

phenoxy,

diloweralkylaminoloweralkyl,

loweralkanoyl,

loweralkenyl and

loweralkynyl or

R₃ and R₄ together with the nitrogen to which they are attached form a 5or 6 membered heterocyclic ring preferably

pyrrolidinyl,

oxazolidinyl,

thiazolidinyl,

pyrazolidinyl,

imidazolidinyl,

piperidyl,

piperazinyl,

thiamorpholinyl, or

morpholinyl.

R₅ is

hydrogen,

halo,

loweralkyl or

loweralkoxy; and

R₉ is

halo,

loweralkyl, or

loweralkoxy.

Another more specific preferred group are the s-triazinones of theformula I-c. ##STR6## wherein: R₃ is

hydrogen,

hydroxy,

loweralkyl,

loweralkoxy, or

diloweralkylaminoloweralkyl; and

R₅ and R₉ are each

loweralkyl,

halo,

haloloweralkyl, or

loweralkoxy; and

R₅ and R₉ may be the same or different.

As employed above and throughout the disclosure, the following terms,unless otherwise indicated, shall be understood to have the followingmeanings:

"alkyl" means a saturated aliphatic hydrocarbon which may be eitherstraight or branched chain preferably having no more than about 20carbon atoms; loweralkyl being preferred; also included are thecycloalkyl groups such as cyclohexyl, cyclopropyl etc. and thecycloalkylalkyl groups such as cyclopropylmethyl and the like.

"loweralkyl" means an alkyl group as above, having 1 to 6 carbon atoms,suitable loweralkyl groups are methyl, ethyl propyl, isopropyl, butyl,sec-butyl, tert-butyl, pentyl and isopentyl.

"cycloalkyl" means an aliphatic monocyclic saturated carbocyclic grouphaving 3 to 6 carbon atoms preferably cyclopropyl, cyclopentyl, andcyclohexyl.

"alkenyl" means an unsaturated aliphatic hydrocarbon having no more thanabout 20 carbon atoms and which contains one or more double bonds andwhich may be straight or branched chain with loweralkenyl, i.e. alkenylof 2 to 6 carbons, being preferred.

"loweralkenyl" means alkenyl of 2 to 6 carbon atoms such as ethylene,propylene, butylene, isobutylene, etc.

"alkynyl" means an unsaturated aliphatic hydrocarbon having no more thanabout 20 carbon atoms and containing one or more triple bonds with loweralkynyl, i.e. alkynyl of 2 to 6 carbons, being preferred.

"loweralkynyl" means alkynyl of 2 to 6 carbon atoms such as propargyl,butynyl, pentynyl, etc.

"aryl" means phenyl and substituted phenyl.

"substituted phenyl" means a phenyl group in which one or more of thehydrogens has been replaced by the same or different substituentsincluding halo, loweralkyl, haloloweralkyl, nitro, amino, acylamino,hydroxy, loweralkoxy, aryl-loweralkoxy acyloxy, cyano, halo-loweralkoxyor loweralkylsulfonyl.

"aralkyl" means an alkyl (preferably a loweralkyl) in which one or morehydrogens is substituted by an aryl moiety (preferably phenyl orsubstituted phenyl), e.g. benzyl, phenethyl, etc.

"5 and 6 membered heterocyclic group" means a 5 or 6 membered ringhaving 1 to 3 hetero atoms which may be nitrogen, oxygen or sulfurincluding pyridyl, 2-pyridyl or 3-pyridyl; pyrimidyl, pyrazolyl,imidazolyl, furyl, thienyl, oxazoneyl, thiazolyl, piperidyl, morpholinyletc. with the pyridyl groups being preferred.

"substituted pyridyl" means a pyridyl in which one or more of thehydrogens on the ring carbons have been replaced by substituents asgiven above with respect to substituted phenyl.

The terms "halo" and "halogen" include all four halogens; namely,fluorine, chlorine, bromine and iodine. The halo alkyls, halophenyl andhalosubstituted pyridyl include groups having more than one halosubstituent which may be the same or different such as trifluoromethyl,1-chloro-2-bromo ethyl, chlorophenyl, 4-chloropyridyl, etc.

The term "acyloxy" is intended to mean an organic acid radical such asacetoxy, propionoxy, and the like.

The term "loweralkanoyl" is intended to include the acid radical of aloweralkanoic acid such as acetyl, propionyl and the like.

Among the compounds of formula I, a particularly preferred group ofnovel compounds are those in which the R₁ substituent is a substitutedphenyl and particularly a phenyl having substituents in the 2 and 6positions (i.e., ortho to the carbon attached to the triazine nitrogen).The preferred phenyl substituents are loweralkyl, loweralkoxy and halo.The preferred R₃ and R₄ substituents are those where R₃ and R₄ are thesame and both are loweralkyl, halo-loweralkyl or loweralkoxy-loweralkyl.The preferred loweralkyl substituents are methyl, ethyl, propyl andisopropyl. The preferred halo substituents are chlorine and bromine. Thepreferred halo-lower alkyl are chloromethyl and trifluoromethyl.

The pyridyl substituents may be either 2-, 3-, or 4-pyridyls; preferredsubstituted pyridyls are those having substituents on the carbon orcarbon atoms vicinal to the carbon attached to the triazine nitrogen.

According to the cyclizing process aspect of this invention, it has beenfound that an amidinourea can be cyclized to the correspondings-triazinone by condensing the amidinourea with an organic reagenthaving an activated methylidene group or capable of forming an activatedmethylidene for example, a methylidene group having at least oneavailable hydrogen atom and a leaving group such as a di-substitutedamino group attached to the methylidene carbon. As organic reagent forcondensing an amidinourea or thiourea starting material to form ans-triazinone or s-triazinthiones there is suitably used an activatedform of an acid amine or an ortho ester or acyl derivative such as aVilsmeir reagent which will bring about acylation and ring closure ofthe amidinourea or thiourea to give s-triazinones and s-triazinthionesof formula I above. The cyclizing process can be used in the same mannerto prepare s-triazinthiones from the corresponding amidinothioureas andit will be understood that in referring to the preparation oftriazinones it is intended to include also the thiones. The reagent maybe the dialkylacetal of a di-alkyl-lowercarboxylic acid amide or thereaction product of a di-alkyl-lowercarboxylic acid amide and analkylating agent. The reagent can be prepared in situ or in advancedepending upon its stability. While this reaction finds applicabilitygenerally for cyclizing amidinoureas it is especially useful inpreparing the novel s-triazinones of this invention. The synthesis oftriazinones according to this invention can employ as starting materialknown amidinoureas or similar starting materials also known in the art,or the materials employed as precursors for cyclizing to forms-triazinones can be readily prepared by analogy to the preparation ofthe known starting materials. Suitable amidinourea starting materialsare those disclosed in U.S. Pat. Nos. 4,060,635 and 4,058,557 and incopending application Ser. No. 671,762 the disclosures of which, aspreviously noted, are incorporated here by reference. Thus, the novelcyclizing process of this invention can be used to derivatizeamidinoureas and thioureas of formula II below. ##STR7## wherein X, R₁,R₃ and R₄ have the same meanings as above.

It should be understood that whereas the structure of the startingmaterials are shown here in a particular configuration for the purposesof illustration it is intended to include the various structural isomersas previously noted. By way of illustration, an alternative structure isshown by formula II-a. Where reference is made to that terminalnitrogens, it is intended to denote the urea nitrogen designated asposition 1 in formula II and the unsubstituted amidino nitrogen.

Thus, there can be prepared in accordance with the process of thisinvention 1,3,5-triazin-2-ones and 1,3,5-triazin-2-thiones utilizing asstarting materials any of the prior art amidinoureas or amidinothioureasincluding the 1-arylamidinoureas and thioureas of Formula III belowwhich constitute a preferred group of starting materials. ##STR8##wherein X and the R₃ and R₄ substituents have the same meanings as thecorresponding substituents on the novel triazines of formula I describedhereinabove and wherein the substituents on the phenyl ring are asfollows: R₅, R₆, R₇, R₈ and R₉ may be the same or different and are:

hydrogen,

halo,

loweralkyl,

haloloweralkyl,

nitro,

loweralkoxy,

hydroxy,

arylloweralkoxy,

acyloxy,

cyano,

haloloweralkoxy or

loweralkylsulfonyl.

Amidinourea starting materials which can be used to prepare a morepreferred group of triazine derivatives are those wherein

R₃ and R₄ are

hydrogen,

hydroxy,

loweralkyl,

loweralkoxy,

haloloweralkyl, or

aralkyl; or

R₃ and R₄ together may form with the nitrogen to which they are attacheda 5-7 atom ring which may include 0-2 hetero atoms of N, O or S.

An even more preferred group of starting materials include those where:

R₅, R₆, R₇, R₈ and R₉ are

hydrogen,

halo,

loweralkyl,

haloloweralkyl,

nitro,

hydroxy or

loweralkoxy.

A still more preferred group of starting materials include those where:

R₅ and R₉ are each

hydrogen,

halo,

loweralkyl,

nitro or

loweralkoxy;

R₆, R₇ and R₈ are each

hydrogen,

hydroxy,

halo,

loweralkyl, or

loweralkoxy; and

R₃ and R₄ are each

hydrogen,

loweralkyl,

hydroxy,

loweralkoxy,

haloloweralkyl, or

acyl.

The most preferred starting materials are those where:

R₅ is

methyl,

ethyl,

chloro or

bromo;

R₆ is hydrogen;

R₇ is hydrogen;

R₈ is hydrogen;

R₉ is

methyl,

ethyl,

nitro,

methoxy,

ethoxy,

chloro,

bromo or

fluoro; and

R₃ and R₄ are each

hydrogen alkyl of C₁ to C₄,

hydroxy,

methoxy,

ethoxy,

chloromethyl,

trifluoromethyl 2,3,2-trifluoroethyl, or

acetyl.

A special embodiment of this invention comprises compounds where thestarting materials have:

X is oxygen; and the phenyl group has

R₅, R₉ loweralkyl, loweralkoxy or halo substitution independently ofeach other;

and one of R₃ and R₄ is hydrogen and the other is

loweralkyl,

haloloweralkyl,

hydroxy,

loweralkoxy or

acyl.

Throughout this disclosure, where reference is made to amidinoureas ortriazinones, it will be understood that the same applies also to thecorresponding amidinothioureas or triazinthiones; and that in allinstances the triazinones and thiones are the1,2-dihydro-1,3,5-triazin-2-ones and 1,2-dihydro-1,3,5-triazin-2-thioneswhatever the abbreviated form of nomenclature that may be used.

The preparation of s-triazinone compounds according to this invention isachieved in general by reacting an appropriate amidinourea oramidinothiourea starting material with an activated form of an acidamide or ortho ester or acyl derivative such as a Vilsmeir reagent whichwill bring about acylation and ring closure of the amidinourea orthiourea to give the corresponding s-triazinone or thiones of the typedescribed above. The reaction can be carried out by simply combining thereactants in a suitable solvent at room temperature with stirring. Thereaction time can be shortened by heating the reaction mixture or byusing elevated pressure or both. The solvent selected should have arelatively high boiling point and low vapor pressure in order to permitthe reaction mixture to be heated above 100° C. Dimethylformamide is aconvenient solvent to use particularly where the cyclizing reagent is adimethylformamide derivative though other organic solvents can also beused. The solvents that can be used include saturated and unsaturatedhydrocarbons, aromatic solvents, alcohols such as methanol and ethanol,halogenated hydrocarbons such as chloroform, carbon tetrachloride,ethylene chloride, or others such as methyl acetate, ethyl acetate,acetonitrile, acetone, ether, acetamide, tetrahydrofuran and the like.Suitable mixtures of solvents can also be used. The reaction ispreferably carried out under substantially anhydrous conditions thoughthe presence of water can be tolerated. If small amounts of water arepresent, the effect can be offset by using an excess of the cyclizingreagent.

The conversion of most amidinoureas to the corresponding s-triazinederivative can be achieved in about 20 minutes or less at temperaturesin the order of 100° C. to 120° C. Higher or lower temperatures can beused if desired and the reaction can be carried out at room temperature.In those cases where the reaction proceeds slowly it can be shortened byheat or pressure or both. The reaction can be readily carried out atatmospheric pressure though if desired, the reaction can be facilitatedby increased pressure. A convenient method for carrying out thecyclizing reaction is by heating the reaction mixture in a sealed vesseland allowing the reaction to proceed under autogenous pressure. Analternative process is by refluxing the reaction mixture for about anhour or more. Where the starting material utilized is the acid additionsalt of an appropriate amidinourea the reaction proceeds almostinstantaneously at room temperature in most cases. However, if theamidinourea starting material is used in the form of the free base, asmall amount of acid preferably a mineral acid particularly hydrochloricacid is desirably added to the reaction mixture. As mentioned above, thereaction is suitably carried out in the presence of a solvent. Thechoice of solvent will in general depend upon the cyclizing reagentused. When using a DMF reagent, the preferred solvents are DMF,DMF-dimethylsulfate complex, or a complex with an alcohol (preferablyiso-propanol) the particular alcohol will depend on the solubility ofthe product obtained.

In most cases the cyclized end product can be recovered by filteringafter direct crystallization from the reaction mixture particularlywhere the solvent has been chosen to facilitate recovery of the endproduct. Where the product does not readily crystallize, the novels-triazinone derivatives can be conveniently isolated in the pure formby solvent extraction using any of the usual organic solvents which arenot miscible with water such as the hydrocarbons, for example, hexane;the chlorinated hydrocarbons, for example, chloroform or carbontetrafluoride; the aromatic solvents such as benzene, xylene, toluene,o-chloro-toluene and the like; ethers such as dioxane; ketones such as 2pentanone etc. The s-triazinone product is extracted into the solventlayer generally after stripping the solvent or concentrating thereaction mixture then shaking with an extracting composition of waterand solvent and removing the solvent component, leaving the by-productin the aqueous layer. The product is recovered by evaporating off thesolvent. If desired, the product can be further purified byrecrystallizing from a suitable organic solvent such as those notedabove. The selection of solvent is not critical and generally thosesolvents which are most readily available will be employed.

The amidinourea starting materials which are derivatized in accordancewith the process aspect of this invention are known materials preparedas previously noted by known methods such as described in U.S. Pat. Nos.4,060,635 and 4,058,557.

The cyclizing reagent employed in the reaction can be any cationicreagent system capable of generating in the reaction mixture astabilized carbonium ion having the oxidation state of an acid or acidamine, preferably an immonium ion. The preferred reagents are thedialkyl carboxylic acid amide dialkyl acetals such as dialkyl formamidedialkyl acetal preferably dimethyl formamide dimethyl acetal; dialkylacetamide dialkyl acetals preferably dimethyl acetamide dimethyl acetal;dialkyl propionamide dialkyl acetal preferably dimethyl propionamidedimethyl acetal. Other carboxylic acid amide derivatives can also beused including substituted derivatives. Since the carboxyl carbon isincorporated into the ring the choice of reagent will determine the R₂substitution in the products of formula I above. Thus, in the case ofthe formamide derivative, R₂ is hydrogen and the resulting triazine isunsubstituted in the 6-position; in the case where the acetamidederivative is used as the cyclizing reagent, R₂ is methyl and theresulting triazine is substituted in the 6-position, and so on. Thepreferred substituents are lower alkyl for which the cyclizing reagentsused are the lower alkanoic acid amide derivatives. Other substituentswithin the meaning of R₂ are obtained by selection of thecorrespondingly substituted alkanoic acid amide in preparing thecyclizing reagent.

In general, the preferred cyclizing reagents are the alkanoic acid amidediacetals of the formula: ##STR9## wherein: R₂ is hydrogen orloweralkyl; and each of R₁₀ through R₁₃ are loweralkyl orhaloloweralkyl.

Other methylidene derivatives that can be used as the cyclizing reagentinclude the combination of an N,N-disubstituted alkanoic acid amide andany strong alkylating agent preferably a strong methylating agent. Anyof the strong alkylating agents known in the art such as methyliodide,methylfluorosulfonate, alkylmethane sulfonates, e.g.,methylmethanesulfonate, and alkyl or dialkyl sulfates, e.g.,dimethylsulfate can be suitably employed though dimethylsulfate ispreferred owing to its ready availability. A preferred cyclizing reagentis a DMF-dimethylsulfate complex particularly DMF-methanemethyl-sulfonate or DMF-methylbenzenesulfonate.

Reagents of the type shown in formula IV above are staple products whichare commercially available or can be prepared in advance. In carryingout the cyclizing reaction, the cyclizing reagent is preferably used inslight excess of the amount required as the stoichiomeric equivalent ofthe amidinourea or amidinothiourea starting material. The preferredreagent is dimethyl formamide dimethylacetal in which casedimethylformamide is a convenient solvent. A particularly preferredreagent system is a mixture of dimethyl formamide and dimethyl sulfateutilizing excess dimethyl formamide as a solvent. Such reagent systemsemploying dimethyl sulfate are prepared as necessary for the cyclizationor can be formed in situ in the reaction mixture by adding the reagentcomponents to the reaction vessel in a suitable solvent or solventmixture. When carrying out the cyclizing reaction with a reagent of thetype shown in formula IV, it is preferred to use as starting material anacid addition salt of the amidinourea or amidinothiourea oralternatively, if the free base is used, then an acid preferably amineral acid such as hydrochloric acid can be added to the reactionmixture. When a reagent system comprising an alkanoic acid amide and astrong alkylating agent is employed, the reagent is itself acidic andthe reaction proceeds readily with the free base as starting material.In such instances it may be advantageous to add a proton scavengingsolvent such as a tertiary amine, e.g., triethylamine or cyclic aminessuch as pyridine. Other miscible solvents can be used along with thepreferred amines e.g., solvents such as triethanolamine, acrylonitrile,ethanol, etc. though dimethyl formamide is preferred. As in the case ofcyclizing with dimethylformamide dimethylacetal the reaction can becarried out at room temperature or at elevated temperatures up to theboiling point of the solvent employed. Preferably, the reaction iscarried out at room temperature i.e., at about 18° to 25° C. Elevatedpressure may also be used. Suitably, the reaction is carried out byrefluxing at the boiling temperature of the solvent. The reactionproduct is easily recovered from the reaction mixture by solventextraction as described above. The reaction proceeds nearlyquantitatively based upon the amidinourea starting material and theproduct can be recovered in nearly quantitative yield, the product canbe further purified by recrystallizing if desired.

Alternatively, some of the triazinones can be prepared by using othercyclizing reagents such as triethyl orthoformate catalyzed with eitherbase or acid though generally such processes are less suitable andconventional cyclizing agents such as phosphonyl chloride and thionylchloride have been found to be unsuited for cyclizing amidinoureas.

Pharmaceutically acceptable salts of the compounds can be obtained asacid addition salts prepared from the corresponding free base byrecrystallizing from a solution of a non-toxic pharmaceuticallyacceptable organic or inorganic acid including strong Lewis acids. Othersalts for example quarternary ammonium salts are prepared by knownmethods for quarternizing organic nitrogen compounds. The non-toxic acidaddition salts that can be conveniently prepared from the novel triazinederivatives of this invention are preferably those prepared from strongacids of low volatility. Among the suitable acids that can be named arethe following:

hydrochloric acid,

hydrobromic acid,

sulfuric acid,

nitric acid,

phosphoric acid,

methane sulfonic acid,

benzene sulfonic acid,

toluene sulfonic acid, etc.

The synthesis of the novel amidinourea and amidinothiourea derivativesof this invention is accomplished in accordance with the novel cyclizingmethod of this invention which in its broad process aspect consists ofcyclizing amidinoureas and amidinothioureas and the like by bridging theterminal nitrogens with a methylidene or substituted methylidene groupderived from a suitable derivatizing reagent.

The novel cyclizing reaction can be illustrated schematically asfollows: ##STR10## wherein X is sulfur or oxygen indicating that thereaction can employ as starting material either an amidinourea oramidinothiourea. The dangling bonds may be substituted by anyappropriate substituent determined by available amidinourea oramidinothourea starting material.

It will be readily apparent that the dangling bonds on the end product1,3,5-triazin-2-one or 1,3,5-triazine-2-thione will be substituted bygroups corresponding to similar substituents on the starting materials.

In accordance with this invention, the process is particularly useful inpreparing compounds of formula I by cyclizing the corresponding startingmaterials and also to prepare compounds of the type shown in formula Iwhere R₁ is an aliphatic group preferably alkyl provided one of R₃ andR₄ is other than hydrogen.

The numerical designations indicate the nomenclature used herein. Itwill be readily understood that alternative naming systems for thesecompounds can be employed.

The novel triazine derivatives prepared in accordance with the method ofthis invention for derivitizing the corresponding amidinourea orthiourea are those in which the substituent in the one position of theamidinourea or amidinothiourea shown schematically above has an aryl orheterocyclic group, preferably compounds of the following formula:##STR11## wherein: X is

oxygen or

sulfur;

R₁ is

aryl,

aralkyl or

a 5 or 6 membered heterocyclic ring attached directly to the triazinenitrogen or attached through an alkylidene bridge preferably having 1 to4 carbon atoms;

R₂ is

hydrogen or

loweralkyl;

R₃ and R₄ are each independently selected from the group consisting of

hydrogen,

hydroxyl,

an aliphatic radical which can be alkyl,

alkenyl,

alkynyl,

cycloalkyl or

any of said aliphatic radicals wherein one or more hydrogen atoms hasbeen replaced by hydroxyl,

alkoxy,

phenoxy,

substituted phenoxy,

cycloalkyl,

haloloweralkyl,

amino,

loweralkylamino or

diloweralkylamino,

phenyl or

substituted phenyl or

a 5 or 6 membered heterocyclic group containing 1 to 3 hetero atomswhich may be nitrogen,

oxygen or sulfur,

loweralkoxy,

phenoxy,

substituted phenoxy,

phenyl,

substituted phenyl or

acyl preferably loweralkanoyl; or

R₃ and R₄ taken together with the nitrogen to which they are attachedmay form a 5 or 6 membered heterocyclic ring containing 1 or 2additional hetero atoms which may be

nitrogen,

oxygen or

sulfur

and the ring may contain 1 or more double bonds; together with theirpharmaceutically acceptable salts.

A preferred group of novel triazines prepared by derivetizingamidinoureas are the compounds of the formula: ##STR12## wherein: R₁ is

phenyl,

substituted phenyl,

pyridyl,

substituted pyridyl or

phenyl-loweralkyl; and

R₃ and R₄ are each separately

hydrogen,

loweralkyl,

haloloweralkyl,

hydroxy,

alkoxy,

alkoxyloweralkyl, or loweralkanoyl; and

their non-toxic pharmaceutically acceptable salts.

A particularly preferred group of novel triazinones are the compounds ofthe formula: ##STR13## wherein: the ortho- substituents on the phenylmoiety designated by R₅ and R₉ are the same or different and are

C₁ to C₄ alkyl,

bromo,

chloro, or

C₁ to C₄ alkoxy; and

the R₃ and R₄ substituents are each

hydrogen,

hydroxyl,

loweralkyl,

haloloweralkyl,

loweralkoxy or

loweralkanoyl.

And those compounds of formula V-b wherein one of R₃ or R₄ is hydrogenare a most preferred group.

Using the general method for cyclizing amidinoureas described above andemploying by way of illustration as the starting material any of theamidinoureas in Tables I, Ia and Ib below, there can be obtained thecorresponding illustrative triazinone of Tables II, II-a and II-b. Thethione analogs and their salts are prepared in the same manner using thecorresponding amidinothiourea as starting material. Examples ofamidinothiourea starting materials and the corresponding thionesobtained by cyclizing in accordance with the method of this inventionare given in Tables III and IV respectively. IV-a, respectively.

TABLE I

1-(2',6'-diethylphenyl)-3-methylamidinourea

1-(2',6'-diethylphenyl)-3-ethylamidinourea

1-(2',6'-diethylphenyl)-3-propylamidinourea

1-(2',6'-diethylphenyl)-3-i-propylamidinourea

1-(2',6'-diethylphenyl)-3-butylamidinourea

1-(2',6'-diethylphenyl)-3-i-butylamidinourea

1-(2',6'-diethylphenyl)-3-pentylamidinourea

1-(2',6'-diethylphenyl)-3-allylamidinourea

1-(2',6'-diethylphenyl)-3-propargylamidinourea

1-(2',6'-diethylphenyl)-3-cyclopropylamidinourea

1-(2',6'-diethylphenyl)-3-methoxyethylamidinourea

1-(2',6'-diethylphenyl)-3-benzyloxyethylamidinourea

1-(2',6'-diethylphenyl)-3-phenethoxyethylamidinuourea

1-(2',6'-diethylphenyl)-3-benzylamidinourea

1-(2',6'-diethylphenyl)-3-(N,N-dimethylamidino)urea

1-(2',6'-diethylphenyl)-3-(N,N-diethylamidino)urea

1-(2',6'-diethylphenyl)-3-(N,N-tetramethyleneamidino)urea

1-(2',6'-diethylphenyl)-3-(N,N-pentamethyleneamidino)urea

1-(2'-methyl-6'-ethylphenyl)-3-methylamidinourea

1-(2'-methyl-6'-ethylphenyl)-3-ethylamidinourea

1-(2'-methyl-6'-ethylphenyl)-3-propylamidinourea

1-(2'-methyl-6'-ethylphenyl)3-i-propylamidinourea

1-(2'-methyl-6'-ethylphenyl)-3-butylamidinourea

1-(2'-methyl-6'-ethylphenyl)3-i-butylamidinourea

1-(2'-methyl-6'-ethylphenyl)3-t-butylamidinourea

1-(2'-methyl-6'-ethylphenyl)-3-pentylamidinourea

1-(2'-methyl-6'-ethylphenyl)-3-allylamidinourea

1-(2'-methyl-6'-ethylphenyl)-3-propargylamidinourea

1-(2'-methyl-6'-ethylphenyl)-3-cyclopropylamidinourea

1-(2'-methyl-6'-ethylphenyl)-3-cyclobutylamidinourea

1-(2'-methyl-6'-ethylphenyl)-3-[N-(3'-cyclopentenyl)amidino]urea

1-(2'-methyl-6'-ethylphenyl)-3-cyclopropylmethylamidinourea

1-(2'-methyl'6'-ethylphenyl)-3-methoxyethylamidinourea

1-(2'-methyl-6'-ethylphenyl)-3-benzyloxyethylamidinourea

1-(2'-methyl-6'-ethylphenyl)-3-phenethoxyethylamidinourea

1-(2'-methyl-6'-ethylphenyl)-3-benzylamidinourea

1-(2'-methyl-6'-ethylphenyl)-3-(N,N-dimethylamidino)urea

1-(2'-methyl-6'-ethylphenyl)-3-(N,N-diethylamidino)urea

1-(2'-methyl-6'-ethylphenyl)-3-(N,N-tetramethyleneamidino)urea

1-(2'-methyl-6'-ethylphenyl)-3-[N,N(3'-methyl-3'-azapentamethylene)amidino]urea

1-(2'-methyl-6'-ethylphenyl)-3-[N,N-(3'-oxapentamethylene)amidino]urea

1-(2'-methyl-6'-chlorophenyl)-3-methylamidinourea

1-(2'-methyl-6'-chlorophenyl)-3-ethylamidinourea

1-(2'methyl-6'-chlorophenyl)-3-propylamidinourea

1-(2'-methyl-6'-chlorophenyl)3-i-propylamidinourea

1-(2'-methyl-6'-chlorophenyl)-3-butylamidinourea

1-(2'-methyl-6'-chlorophenyl)-3-i-butylamidinourea

1-(2'-methyl-6'-chlorophenyl)-3-t-butylamidinourea

1-(2'-methyl-6'-chlorophenyl)-3-pentylamidinourea

1-(2'-methyl-6'-chlorophenyl)-3-allylamidinourea

1-(2'-methyl-6'-chlorophenyl)-3-propargylamidinourea

1-(2'-methyl-6'-chlorophenyl)-3-cyclobutylamidinourea

1-(2'-methyl-6'-chlorophenyl)-3-cyclohexylamidinourea

1-(2'-methyl-6'-chlorophenyl)-3-benzylamidinourea

1-(2'-methyl-6'-chlorophenyl)-3-methoxyethylamidinourea

1-(2'-methyl-6'-chlorophenyl)-3-benzyloxyethylamidinourea

1-(2'-methyl-6'-chlorophenyl)-3-phenethoxyethylamidinourea

1-(2'-methyl-6'-chlorophenyl)-3-(N,N-diethylamidino)urea

1-(2'-methyl-6'-chlorophenyl)-3-(N,N-diethylamidino)urea

1-(2'-methyl-6'-chlorophenyl)-3-(N,N-pentamethyleneamidino)urea

1-(2'-methyl-6'-bromophenyl)-3-methylamidinourea

1-(2'-methyl-6'-bromophenyl)-3-ethylamidinourea

1-(2'-methyl-6'-bromophenyl)-3-propylamidinourea

1-(2''-methyl-6'-bromophenyl)-3-i-propylamidinourea

1-(2-methyl-6'-bromophenyl)-3-butylamidinourea

1-(2'-methyl-6'-bromophenyl)-3-t-butylamidinourea

1-(2'-methyl-6'-bromophenyl)-3-pentylamidinourea

1-(2'-methyl-6'-bromophenyl)-3-hexylamidinourea

1-(2'-methyl-6'-bromophenyl)-3-propargylamidinourea

1-(2'-methyl-6'-bromophenyl)-3-allylamidinourea

1-(2'-methyl-6'-bromophenyl)-3-methoxyethylamidinourea

1-(2'-methyl-6'-bromophenyl)-3-benzyloxyethylamidinourea

1-(2'-methyl-6'-bromophenyl)-3-phenethoxyethylamidinourea

1-(2'-methyl-6'-bromophenyl)-3-(N,N-dimethylamidino)urea

1-(2'-methyl-6'-bromophenyl)-3-(N,N-diethylamidino)urea

1-(2'-methyl-6'-bromophenyl)-3-(N-methyl-N-ethylamidino)urea

1-(2'-methyl-6'-bromophenyl)-3-(N,N-tetramethyleneamidino)urea

1-(2'-methyl-6'-bromophenyl)-3-(N,N-pentamethyleneamidino)urea

1-(2'-methyl-6'-bromophenyl)-3-(N,N-hexamethyleneamidino)urea

1-(2'-ethyl-6'-chlorophenyl)-3-methylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-3-ethylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-3-propylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-3-butylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-3-i-butylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-3-pentylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-3-allylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-3-propargylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-3-methoxyethylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-3-benzyloxyethylamidinourea

1-(2'-ethyl-6'-chlorophenyl)-3-(N,N-dimethylamidino)urea

1-(2'-ethyl-6'-chlorophenyl)-3-(N,N-diethylamidino)urea

1-(2'-ethyl-6'-chlorophenyl)-3-(N,N-tetramethyleneamidino)urea

1-(2'-methyl-6'-fluorophenyl)-3-methylamidinourea

1-(2',6'-dimethyl-4'-hydroxyphenyl)-3-methylamidinourea

1-(2',6'-diethyl-4'-hydroxyphenyl)-3-methylamidinourea

1-(2'-methyl-6'-chloro-4'-hydroxyphenyl)-3-methylamidinourea

1-(2'-methyl-6'-bromo-4'-hydroxyphenyl)-3-methylamidinourea

1-(2'-methyl-6'-fluoro-4'-hydroxyphenyl)-3-methylamidinourea

1-(2'-methyl-6'-ethyl-4'-hydroxyphenyl)-3-methylamidinourea

1-(2'-ethyl-6'-chloro-4'-hydroxyphenyl)-3-methylamidinourea

1-(2'-ethyl-6'-bromo-4'-hydroxyphenyl)-3-methylamidinourea

1-(2'-ethyl-6'-fluoro-4'-hydroxyphenyl)-3-methylamidinourea

1-(2',6'-dimethyl-4'-aminophenyl)-3-methylamidinourea

1-(2',6'-diethyl-4'-aminophenyl)-3-methylamidinourea

1-(2'-methyl-6'-ethyl-4'-aminophenyl)-3-methylamidinourea

1-(2'-methyl-6'-chloro-4'-aminophenyl)-3-methylamidinourea

1-(2'-methyl-6'-bromo-4'-aminophenyl)-3-methylamidinourea

1-(2'-methyl-6'-fluoro-4'-aminophenyl)-3-methylamidinourea

1-(2'-ethyl-6'-chloro-4'-aminophenyl)-3-methylamidinourea

1-(2'-ethyl-6'-bromo-4'-aminophenyl)-3-methylamidinourea

1-(2'-ethyl-6'-fluoro-4'-aminophenyl)-3-methylamidinourea

1-(2',6'-dimethyl-4'-acetylamino)-3-methylamidinourea

1-(2',6'-diethyl-4'-acetylamino)-3-methylamidinourea

1-(2'-methyl-6'-ethyl-4'-acetylamino)-3-methylamidinourea

1-(2'-methyl-6'-chloro-4'-acetylamino)-3-methylamidinourea

1-(2'-methyl-6'-bromo-4'-acetylamino)-3-methylamidinourea

1-(2'-methyl-6'-fluoro-4'-acetylamino)-3-methylamidinourea

1-(2'-ethyl-6'-chloro-4'-acetylamino)-3-methylamidinourea

1-(2'-ethyl-6'-bromo-4'-acetylamino)-3-methylamidinourea

1-(2'-ethyl-6'-fluoro-4'-acetylamino)-3-methylamidinourea

1-(2',6'-diethyl-4'-nitrophenyl)-3-methylamidinourea hydrochloride

1-(4'-amino-2',6'-diethylphenyl)-3-methylamidinourea dihydrochloride

1-(2',6'-dimethyl-4'-aminophenyl-3-methylamidinourea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N-diethylamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N-ethyl-N-methylamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N-methyl-N-propylamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N-methyl-N-butylamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N-dipropylamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N-ethyl-N-propylamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N-methyl-N-benzyloxypropylamidino)ureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N-methyl-N-phenethoxyethylamidino)ureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N-methyl-N-benzyloxyethylamidino)ureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N-tetrametnyleneamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N-pentamethyleneamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N-hexamethyleneamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-[N,N-(3'-oxapentamethylene)amidino]ureahydrochloride

1-(2',6'-dimethylphenyl)-3-[N,N-(3'-methyl-3'-azapentamethylene)amidino]ureahydrochloride

1-(2',6'-dimethylphenyl)-3-[N,N-(3'-methyl-3'-azahexemethylene)amidino]ureahydrochloride

1-(2',6'-dimethylphenyl)-3-[N,N-(3'-thiapentamethylene)amidino]ureahydrochloride

1-(2',6'-dimethylphenyl)-3-[N,N-(2'-thiatetramethylene)amidino]ureahydrochloride

1-(2',6'-dimethylphenyl)-3-[N-(2'-butenyl)amidino]urea hydrochloride

1-(2',6'-dimethylphenyl)-3-[N-(2'-butynyl)amidino]urea hydrochloride

1-(2',6'-dimethylphenyl)-3-[N-(3'-butynyl)amidino]urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N-methyl-N-allylamidino)urea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N-methyl-N-propargylamidino)ureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N-methyl-N-cyclopropylamidino)ureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N-methylamidino)urea

1-(2',6'-dimethylphenyl)-3-(N,N-dimethylamidino)urea

1-(2'-methyl-6'-methoxyphenyl)-3-(N-methylamidino)urea

1-(2'-methylphenyl)-3-(N-methylamidino)urea

1-(2',4',6'-trimethylphenyl)-3-(N-methylamidino)urea

1-(2'-methyl-4'-bromo-6'-chlorophenyl)-3-(N-methylamidino)urea

1-(2'-chloro-6'-fluorophenyl)-3-(N-methylamidino)urea

1-(2',5'-dichlorophenyl)-3-(N-methylamidino)urea

1-(2'-chloro-6'-bromophenyl)-3-(N-methylamidino)urea

1-(2'-chloro-5'-bromophenyl)-3-(N-methylamidino)urea

1-(2'-chloro-5'-fluorophenyl)-3-(N-methylamidino)urea

1-(2'-fluoro-5'-chlorophenyl)-3-(N-methylamidino)urea

1-(2'-fluoro-5'-bromophenyl)-3-(N-methylamidino)urea

1-(2',4',6'-triethylphenyl)-3-(N-methylamidino)urea

1-(2',4'-dimethyl-6'-ethylphenyl)-3-(N-methylamidino)urea

1-(2',6'-dimethyl-4'-ethylphenyl)-3-(N-methylamidino)urea

1-(2'-ethylphenyl)-3-(N-methylamidino)urea

1-(2'-ethyl-4'-bromo-6'-chlorophenyl)-3-(N-methylamidino)urea

1-(2'-ethyl-6'-methoxyphenyl)-3-(N-methylamidino)urea

1-(2'-methyl-6'-ethoxyphenyl)-3-(N-methylamidino)urea

1-(2',6'-dimethylphenyl)-3-(N-ethylamidino)urea

1-(2',6'-dimethylphenyl)-3-(N-propylamidino)urea

1-(2',6'-dimethylphenyl)-3-(N-i-propylamidino)urea

1-(2',6'-dimethylphenyl)-3-(N-butylamidino)urea

1-(2',6'-dimethylphenyl)-3-(N-i-butylamidino)urea

1-(2',6'-dimethylphenyl)-3-(N-sec-butylamidino)urea

1-(2',6'-dimethylphenyl)-3-(N-t-butylamidino)urea

1-(2',6'-dimethylphenyl)-3-(N-pentylamidino)urea

1-(2',6'-dimethylphenyl)-3-(N-hexylamidino)urea

1-(2',6'-dimethylphenyl)-3-(N-heptylamidino)urea

1-(2',6'-dimethylphenyl)-3-(N-cyclopropylamidino)urea

1-(2',6'-dimethylphenyl)-3-(N-cyclobutylamidino)urea

1-(2',6'-dimethylphenyl)-3-(N-cyclopentylamidino)urea

1-(2',6'-dimethylphenyl)-3-(N-cyclohexylamidino)urea

1-(2',6'-dimethylphenyl)-3-(N-phenylamidino)urea

1-(2',6'-dimethylphenyl)-3-(N-benzylamidino)urea

1-(2',6'-dimethylphenyl)-3-(N-phenethylamidino)urea

1-(2',6'-dimethylphenyl)-3-(N-methyl-N-benzylamidino)urea

1-(2',6'-dimethylphenyl)-3-(N,N-dibenzylamidino)urea

1-(2'-methyl-6'-chlorophenyl)-3-amidinourea

1-(2'-methyl-6'-fluorophenyl)-3-amidinourea

1-(2'-methyl-6'-bromophenyl)-3-amidinourea

1-(2'-methyl-6'-iodophenyl)-3-amidinourea

1-(2'-methyl-6'-methoxyphenyl)-3-amidinourea

1-(2'-methyl-6'-ethoxyphenyl)-3-amidinourea

1-(2'-methyl-6'-ethylphenyl)-3-amidinourea

1-(2'-methyl-6'-propylphenyl)-3-amidinourea

1-(2'-methyl-6'-i-propylphenyl)-3-amidinourea

1-(2'-methyl-6'-butylphenyl)-3-amidinourea

1-(2'-methyl-6'-cyano phenyl)-3-amidinourea

1-(2'-methyl-6'-trifluoromethylphenyl)-3-amidinourea

1-(2'-methyl-6'-nitrophenyl)-3-amidinourea

1-(2'-methyl-6'-methylsulfonylphenyl)-3-amidinourea

1-(2'-ethyl-6'-chlorophenyl)-3-amidinourea

1-(2'-ethyl-6'-fluorophenyl)-3-amidinourea

1-(2'-ethyl-6'-bromophenyl)-3-amidinourea

1-(2'-ethyl-6'-methoxyphenyl)-3-amidinourea

1-(2'-ethyl-6'-ethoxyphenyl)-3-amidinourea

1-(2',6'-diethylphenyl)-3-amidinourea

1-(2'-ethyl-6'-propylphenyl)-3-amidinourea

1-(2'-ethyl-6'-trifluoromethylphenyl)-3-amidinourea

1-(2'-propyl-6'-chlorophenyl)-3-amidinourea

1-(2'-propyl-6'-bromophenyl)-3-amidinourea

1-(2'-propyl-6'-methoxyphenyl)-3-amidinourea

1-(2'-propyl-6'-ethoxyphenyl)-3-amidinourea

1-(2',6'-dipropylphenyl)-3-amidinourea

1-(2'-i-propyl-6'-chlorophenyl)-3-amidinourea

1-(2',6'-dichlorophenyl)-3-amidinourea

1-(2'-chloro-3'-methylphenyl)-3-amidinourea

1-(2'-chloro-4'-methylphenyl)-3-amidinourea

1-(2'-chloro-5'-methylphenyl)-3-amidinourea

1-(2'-chloro-5'-trifluoromethylphenyl)-3-amidinourea

1-(2'-chloro-6'-fluorophenyl)-3-amidinourea

1-(2',6'-difluorophenyl)-3-amidinourea

1-(2'-propylphenyl)-3-amidinourea

1-(4'-trifluoromethylphenyl)-3-amidinourea

1-(3',4'-dimethoxyphenyl)-3-amidinourea

1-(3',4',5'-trimethoxyphenyl)-3-amidinourea

1-(3',4'-diethoxyphenyl)-3-amidinourea

1-(2',4'-dimethylphenyl)-3-amidinourea

1-(2',4'-diethylphenyl)-3-amidinourea

1-(2'-methyl-4'-ethylphenyl)-3-amidinourea

1-(2'-methyl-4'-chlorophenyl)-3-amidinourea

1-(2'-ethyl-4'-chlorophenyl)-3-amidinourea

1-(2',4',6'-trimethylphenyl)-3-amidinourea

1-(2',4'-dimethyl-6'-ethylphenyl)-3-amidinourea

1-(2',4'-dimethyl-6'-trifluoromethylphenyl)-3-amidinourea

1-(2',4'-dimethyl-6'-nitrophenyl)-3-amidinourea

1-(2',4'-dimethyl-6'-methoxyphenyl)-3-amidinourea

1-(2',6'-dimethyl-4'-chlorophenyl)-3-amidinourea

1-(2',6'-dimethyl-4'-bromophenyl)-3-amidinourea

1-(2',6'-dimethyl-4'-methoxyphenyl)-3-amidinourea

1-(2'-methyl-4',6'-dichlorophenyl)-3-amidinourea

1-(2'-methyl-4',6'-difluorophenyl)-3-amidinourea

1-(2'-methyl-4'-fluoro-6'-bromophenyl)-3-amidinourea

1-(2'-methyl-4'-chloro-6'-trifluoromethylphenyl)-3-amidinourea

1-(2'-methyl-4'-trifluoromethyl-6'-chlorophenyl)-3-amidinourea

1-(2'-ethyl-4',6'-dichlorophenyl)-3-amidinourea

1-(2',6'-diethyl-4'-chlorophenyl)-3-amidinourea

1-(2',6'-diethyl-4'-bromophenyl)-3-amidinourea

1-(2',6'-diethyl-4'-fluorophenyl)-3-amidinourea

1-(2'-chloro-6'-methylphenyl)-3-amidinourea

1-(2',6'-dimethylphenyl)-3-amidinourea

1-(2',6'-diethylphenyl)-3-amidinourea

1-(2'-methyl-6'-methoxyphenyl)-3-amidinourea

1-(2'-methyl-6'-chlorophenyl)-3-amidinourea

1-(2'-methylphenyl)-3-amidinourea

1-(2'-chloro-6'-fluorophenyl)-3-amidinourea

1-(2'-methyl-6'-ethylphenyl)-3-amidinourea

1-(2',4',6'-trimethylphenyl)-3-amidinourea

1-(2'-methyl-6'-methoxyphenyl)-3-(N-methylamidino)urea

1-(2'-methylphenyl)-3-(N-methylamidino)urea

1-(2',4',6'-trimethylphenyl)-3-(N-methylamidino)urea

1-(2'-methyl-4'-bromo-6'-chlorophenyl)-3-(N-methylamidino)urea

1-(2'-chloro-6'-fluorophenyl)-3-(N-methylamidino)urea

1-(2',5'-dichlorophenyl)-3-(N-methylamidino)urea

1-(2'-chloro-6'-bromophenyl)-3-(N-methylamidino)urea

1-(2'-chloro-5'-bromophenyl)-3-(N-methylamidino)urea

1-(2'-chloro-5'-fluorophenyl)-3-(N-methylamidino)urea

1-(2'-fluoro-5'-chlorophenyl)-3-N-methylamidino)urea

1-(2'-fluoro-5'-bromophenyl)-3-(N-methylamidino)urea

1-(2',4',6'-triethylphenyl)-3-(N-methylamidino)urea

1-(2',4'-dimethyl-6'-ethylphenyl)-3-(N-methylamidino)urea

1-(2',6'-dimethyl-4'-ethylphenyl)-3-(N-methylamidino)urea

1-(2'-ethylphenyl)-3-(N-methylamidino)urea

1-(2'-ethyl-4'-bromo-6'-chlorophenyl)-3-(N-methylamidino)urea

1-(2'ethyl-6'-methoxyphenyl)-3-(N-methylamidino)urea

1-(2'-methyl-6'-ethoxyphenyl)-3-(N-methylamidino)urea

1-(2',6'-dimethylphenyl)-3-[N-(2',6'-dimethylphenyl)amidino]urea

1-(2',6'-dimethylphenyl)-3-[N-(2'methylpheynl)amidino]yrea

1-(2',6'-dimethylphenyl)-3-[N-(2',6'-diethylphenyl)amidino]urea

1-(2',6'-dimethylphenyl)-3-[N-(2'methyl-6'-chlorophenyl)amidino]urea

1-(2',6'-dimethylphenyl)-3-[N-(2',4',6'-trimethylphenyl)amidino]urea

TABLE II

1-(2',6'-diethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'6'-diethylphenyl)-4-ethylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-diethylphenyl)-4-propylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-diethylphenyl)-4-i-propylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-diethylphenyl)-4-butylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-diethylphenyl)-4-i-butylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-diethylphenyl)-4-pentylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-diethylphenyl)-4-allylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-diethylphenyl)-4-propargylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-diethylphenyl)-4-cyclopropylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-diethylphenyl)-4-methoxyethylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-diethylphenyl)-4-benzyloxyethylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-diethylphenyl)-4-phenethoxyethylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-diethylphenyl)-4-benzylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-diethylphenyl)-4-(N,N-dimethylamino)-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-diethylphenyl)-4-(N,N-diethylamino)-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-diethylphenyl)-4-(N-pyrrolidinyl)-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-diethylphenyl)-4-(N-piperidyl)-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-ethyl-phenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-ethyl-phenyl)-4-ethylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-ethyl-phenyl)-4-propylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-ethyl-phenyl)-4-i-propylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'ethyl-phenyl)-4-butylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'methyl-6'ethyl-phenyl)-4-i-butylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'methyl-6'-ethyl-phenyl)-4-t-butylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-ethyl-phenyl)-4-pentylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'methyl-6'ethyl-phenyl)-4-allylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'methyl-6'-ethyl-phenyl)-4-propargylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-ethylphenyl)-4-cyclopropylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'ethyl-phenyl)-4-cyclobutylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-ethyl-phenyl)-4-cyclopenten-3-yl-amino-1,3,5-triazin-2-one

1-(2'methyl-6'ethyl-phenyl)-4-cyclopropylmethylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'methyl-6'-ethyl-phenyl)-4-methoxyethylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-ethyl-phenyl)-4-benzyloxyethylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'methyl-6'-ethyl-phenyl)-4-phenethoxyethylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-ethyl-phenyl)-4-benzylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'methyl-6'-ethyl-phenyl)-4-(N,N-dimethylamino)-1,2-dihydro-1,3,5-triazin-2-one

1-(2'methyl-6'-ethyl-phenyl)-4-(N,N-diethylamino)-1,2-dihydro-1,3,5-triazin-2-one

1-(2'methyl-6-ethyl-phenyl)-4-(N-pyrrolidinyl)-1,2-dihydro-1,3,5-triazin-2-one

1-(2'methyl-6'-ethyl-phenyl)-4-[3-(N-methyl-piperidyl)]-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-chlorophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'methyl-6'-ethylphenyl)-4-(N-morpholinyl)-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-chlorophenyl)-4-ethylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-chlorophenyl)-4-propylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-chlorophenyl)-4-i-propylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-chlorophenyl-4-butylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-chlorophenyl)-4-i-butylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-chlorophenyl)-4-t-butylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-chlorophenyl)-4-pentylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-chlorophenyl)-4-pentylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-chlorophenyl)-4-propargylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-chlorophenyl)-4-cyclobutylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6-chlorophenyl)-4-cyclohexylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-chlorophenyl)-4-benzylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-chlorophenyl)-4-methoxyethylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-chlorophenyl)-4-benzyloxyethylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-chlorophenyl)-4-phenethoxyethylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-chlorophenyl)-4-(N,N-diethylamino)-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-chlorophenyl)-4-(N-piperidinyl)-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-bromophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-bromophenyl)-4-ethylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-bromophenyl-4-propylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-bromophenyl)-4-i-propylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-bromophenyl)-4-butylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-bromophenyl-4-t-butylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-bromophenyl)-4-pentylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-bromophenyl)-4-hexylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2-methyl-6'-bromophenyl)-4-propargylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-bromophenyl)-4-allylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-bromophenyl)-4-methoxyethylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-bromophenyl)-4-benzyloxyethylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-bromophenyl)-4-phenethoxyethylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-bromophenyl)-4-(N,N-dimethylamino)-1,2-dihydro-1,3,5-triazine-2-one

1-(2'-methyl-6'-bromophenyl)-4-(N,N-diethylamino)-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-bromophenyl)-4-(N-methyl-N-ethylamino)-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-bromophenyl)-4-(N-pyrrolidyl)-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-bromophenyl)-4-(N-piperidyl)-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-bromophenyl)-4-(N-azepinyl)-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-ethyl-6'-chlorophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-ethyl-6'-chlorophenyl)-4-ethylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-ethyl-6'-chlorophenyl)-4-propylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-ethyl-6'-chlorophenyl)-4-butylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-ethyl-6'-chlorophenyl)-4-i-butylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-ethyl-6'-chlorophenyl)-4-pentylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-ethyl-6'-chlorophenyl)-4-allylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-ethyl-6'-chlorophenyl)-4-propargylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-ethyl-6'-chlorophenyl)-4-methoxyethylamino-1,2-dihydro-1,3,5-triazin-2-one1-(2'-ethyl-6'-chlorophenyl)-4-benzyloxyethylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-ethyl-6'-chlorophenyl)-4-(N,N-dimethylamino)-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-ethyl-6'-chlorophenyl)-4-(N,N-diethylamino)-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-ethyl-6'-chlorophenyl)-4-(N-pyrrolidinyl)-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-fluorophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethyl-4'-hydroxyphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-diethyl-4'-hydroxyphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-chloro-4'-hydroxyphenyl)-4-methylamino-1,2-hydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-bromo-4'-hydroxyphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-fluoro-4'-hydroxyphenyl-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-ethyl-4'-hydroxyphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-ethyl-6'-chloro-4'-hydroxyphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one1-(2'-ethyl-6'-bromo-4'-hydroxyphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-ethyl-6'-fluoro-4'-hydroxyphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethyl-4'-aminophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-diethyl-4'-aminophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-ethyl-4'-aminophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-ethyl-4'-aminophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-ethyl-4'-aminophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-bromo-4'-aminophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-fluoro-4'-aminophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-ethyl-6'-chloro-4'-aminophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one1-(2'-ethyl-6'-bromo-4'-aminophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-ethyl-6'-fluoro-4'-aminophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethyl-4'-acetylamino)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-diethyl-4'-acetylamino)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-ethyl-4'-acetylamino)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-chloro-4'-acetylamino)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-bromo-4'-acetylamino)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-fluoro-4'-acetylamino)-4-methylamino-1,2-hydro-1,3,5-triazin-2-one

1-(2'-ethyl-6'-chloro-4'-acetylamino)-4-methylamino-1,2-hydro-1,3,5-triazin-2-one

1-(2'-ethyl-6'-bromo-4'-acetylamino)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-ethyl-6'-fluoro-4'-acetylamino-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-diethyl-4'-nitrophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(4'-amino-2',6'-diethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethyl-4'-aminophenyl-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-(N,N-diethylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-(N-ethyl-N-methylamino)-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-(N-methyl-N-propylamino)-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-(N-methyl-N-butylamino)-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-(N,N-dipropylamino)-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-(N-ethyl-N-propylamino)-1,2-dihydro-1,3,5-triazin-2-one1-(2',6'-dimethylphenyl)-4-(N-methyl-N-benzyloxypropylamino)-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-(N-methyl-N-phenethoxyethylamino)-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-(N-methyl-N-benzyloxyethylamino)-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-(N-pyrrolidinyl)-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-(N-piperidyl)-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)4-(N-azipinyl)-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-(N-morpholinyl)-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethyl)-4-[3-(N-methylpiperidyl]-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-[3-(N-methylacepinyl]-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-[N-(3-thiomorpholinyl]-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-[N(3-thioazolinyl)]-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)4-(2-butenylamino)-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-(2-butylnylamino)-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-(3-butynylamino)-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-(N-methyl-N-allylamino)-1,2-dihydro-1,3,5-griazin-2-one

1-(2',6'-dimethylphenyl)-4-(N-methyl-N-propargylamino)-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-(N-methyl-N-cyclopropylamino)-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-(N,N-dimethylamino)-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-methoxyphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',4',6'-trimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-4'-bromo-6'-chlorophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-chloro-6'-fluorophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',5'-dichlorophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-chloro-6'-bromophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-chloro-5'-bromophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-chloro-5'-fluorophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-fluoro-5'-chlorophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-fluoro-5'-bromophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',5',6'-triethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',4'-dimethyl-6'-ethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethyl-4'-ethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-ethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one1-(2'-ethyl-4'-bromo-6'-chlorophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-on3

1-(2'-ethyl-6'-methoxyphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-ethoxyphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-ethylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-propylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-(i-propylamino)1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-butylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-(i-butylamino)-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-(sec-butylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-(t-butylamino)-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-pentylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-hexylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-heptylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-cyclopropylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-cyclobutylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-cyclopentylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-cyclohexylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-anilino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-benzylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-phenethylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-(N-methyl-N-benzylamino)-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-(N,N-dibenzylamino)-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-chlorophenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-fluorophenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-bromophenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-indophenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-methoxyphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-ethoxyphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-ethylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-propylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-i-propylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-butylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-cyano phenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'methyl-6'-trifluoromethylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-nitrophenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-methylsulfonylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-ethyl-6'-chlorophenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-ethyl-6'-fluorophenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-ethyl-6'-bromophenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-ethyl-6'-methoxyphenyl)-4-amino-1,2-dihydro-1,3,t-triazin-2-one

1-(2'-ethyl-6'-ethoxyphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-diethylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-ethyl-6'-propylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-ethyl-6'-trifluoromethylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-propyl-6'-chlorophenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-propyl-6'-bromophenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-propyl-6-methoxyphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-propyl-6'-ethoxyphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dipropylphenyl)4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-i-propyl-6'-chlorophenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dichlorophenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-chloro-3'-methylphenyl)-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-chloro-4'-methylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-chloro-5'-methylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-chloro-5'-trifluoromethylphenyl)-4-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-chloro-6'-fluorophenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-difluorophenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-propylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-on3

1-(4'-trifluoromethylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(3',4'-dimethoxyphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(3',4',5',-trimethoxyphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(3',4',diethoxyphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2

1-(2,4'-dimethylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2,4'-diethylphenyl)4-4amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-4'-ethylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-4'-chlorophenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-ethyl-4'-chlorophenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',4',6'-trimethylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',4'-dimethyl-6'-ethylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',4'-dimethyl-6'-trifluoromethylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',4'-dimethyl-6'-nitrophenyl-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',4'-dimethyl-6'-methoxyphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethyl-4'-chlorophenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethyl-4'-bromophenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethyl-4'-methoxyphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-4',6'-dichlorophenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-4',6'-difluorophenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-4'-fluoro-6'-bromophenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-4'-chloro-6'-trifluoromethylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-4'-trifluoromethyl-6-chlorophenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-ethyl-4',6'-dichlorophenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-diethyl-4'-chlorophenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-diethyl-4'-bromophenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-diethyl-4'-fluorophenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-chloro-6'-methylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-diethylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-methoxyphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-chlorophenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-chloro-6'-fluorophenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-ethylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',4',6'-trimethylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-methoxyphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',4',6'-trimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-4'-bromo-6'-chlorophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-chloro-6'-fluorophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',5'-dichlorophenyl-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-chloro-6'-bromophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-chloro-5'-bromophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-chloro-5'-fluorophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-fluoro-5'-chlorophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-fluoro-5'-bromophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',4',6'-triethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',4'-dimethyl-6'-ethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'6'-dimethyl-4'-ethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-ethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-ethyl-4'-bromo-6'-chlorophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-ethyl-6'-methoxyphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2'-methyl-6'-ethoxyphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-(2',6'-dimethylphenylamino)-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-(2'-methylphenylamino)-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-(2'6'-diethylphenylamino)-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-(2'-methyl-6'-chlorophenylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-4-(2',4',6'-trimethylphenylamino)-1,2-dihydro-1,3,5-triazin-2-one

TABLE III

1-(2',6'-diethylphenyl)-3-methylamidinothiourea

1-(2',6'-diethylphenyl)-3-ethylamidinothiourea

1-(2',6'-diethylphenyl)-3-i-propylamidinothiourea

1-(2',6'-diethylphenyl)-3-pentylamidinothiourea

1-(2',6'-diethylphenyl)-3-allylamidinothiourea

1-(2',6'-diethylphenyl)-3-propargylamidinothiourea

1-(2',6'-diethylphenyl)-3-cyclopropylamidinothiourea

1-(2',6'-diethylphenyl)-3-methoxyethylamidinothiourea

1-(2',6'-diethylphenyl)-3-benzyloxyethylamidinothiourea

1-(2',6'-diethylphenyl)-3-phenethoxyethylamidinothiourea

1-(2',6'-diethylphenyl)-3-benzylamidinothiourea

1-(2',6'-diethylphenyl)-3-(N,N-dimethylamidino)thiourea

1-(2',6'-diethylphenyl)-3-(N,N-tetramethyleneamidino)thiourea

1-(2'-methyl-6'-ethylphenyl)-3-methylamidinothiourea

1-(2'-methyl-6'-ethylphenyl)-3-t-butylamidinothiourea

1-(2'-methyl-6'-ethylphenyl)-3-propargylamidinothiourea

1-(2'-methyl-6'-ethylphenyl)-3-cyclopropylamidinothiourea

1-(2'-methyl-6'-ethylphenyl)-3-[N-(3'-cyclopentenyl)amidino]thiourea

1-(2'-methyl-6'-ethylphenyl)-3-phenethoxyethylamidinothiourea

1-(2'-methyl-6'-ethylphenyl-3-benzylamidinothiourea

1-(2'-methyl-6'-ethylphenyl)-3-[N,N-diethylamidino)thiourea

1-(2'-methyl-6'-ethylphenyl)-3-[N,N(3'-methyl-3'-azapentamethylene)amidino]thiourea

1-(2'-methyl-6'-ethylphenyl)-3-[N,N-(3'-oxapentamethylene)amidino]thiourea

1-(2'-methyl-6'-chlorophenyl)-3-methylamidinothiourea

1-(2'-methyl-6'-chlorophenyl)-3-ethylamidinothiourea

1-(2'-methyl-6'-chlorophenyl)-3-propargylamidinothiourea

1-(2'-methyl-6'-chlorophenyl)-3-cyclohexylamidinothiourea

1-(2'-methyl-6'-chlorophenyl)-3-benzylamidinothiourea

1-(2'-methyl-6'-chlorophenyl)-3-methoxyethylamidinothiourea

1-(2'-methyl-6'-chlorophenyl)-3-(N,N-diethylamidino)thiourea

1-(2'-methyl-6'-chlorophenyl)-3-(N,N-pentamethyleneamidino)thiourea

1-(2'-methyl-6'-bromophenyl)-3-ethylamidinothiourea

1-(2'-ethyl-6'-chlorophenyl)-3-methylamidinothiourea

1-(2'-ethyl-6'-chlorophenyl)-3-benzyloxyethylamidinothiourea

1-(2'-methyl-6'-fluorophenyl)-3-methylamidinothiourea

1-(2',6'-dimethyl-4'-hydroxyphenyl)-3-methylamidinothiourea

1-(2',6'-diethyl-4'-hydroxyphenyl)-3-methylamidinothiourea

1-(2'-methyl-6'-chloro-4'-hydroxyphenyl)-3-methylamidinothiourea

1-(2',6'-dimethyl-4'-aminophenyl)-3-methylamidinothiourea

1-(2',6'-diethyl-4'-aminophenyl)-3-methylamidinothiourea

1-(2',6'-dimethyl-4'-acetylamino)-3-methylamidinothiourea

1-(2'-methyl-6'-chloro-4'-acetylamino)-3-methylamidinothiourea

1-(2',6'-diethyl-4'-nitrophenyl)-3-methylamidinothiourea hydrochloride

1-(2',6'-dimethyl-4'-aminophenyl-3-methylamidinothiourea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N-diethylamidino)thiourea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N-dipropylamidino)thiourea hydrochloride

1-(2',6'-dimethylphenyl)-3-(N-methyl-N-benzyloxyethylamidino)thioureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N,N-tetramethyleneamidino)thioureahydrochloride

1-(2',6'-dimethylphenyl)-3-(N-methylamidino)thiourea

1-(2',6'-dimethylphenyl)-3-(N,N-dimethylamidino)thiourea

1-(2',4',6'-trimethylphenyl)-3-(N-methylamidino)thiourea

1-(2',5'-dichlorophenyl)-3-(N-methylamidino)thiourea

1-(2',4',6'-triethylphenyl)-3-(N-methylamidino)thiourea

1-(2'-ethylphenyl)-3-(N-methylamidino)thiourea

1-(2',6'-dimethylphenyl)-3-(N-ethylamidino)thiourea

1-(2',6'-dimethylphenyl)-3-(N-propylamidino)thiourea

1-(2',6'-dimethylphenyl)-3-(N-i-propylamidino)thiourea

1-(2',6'-dimethylphenyl)-3-(N-t-butylamidino)thiourea

1-(2',6'-dimethylphenyl)-3-(N-cyclohexylamidino)thiourea

1-(2',6'-dimethylphenyl)-3-(N-phenylamidino)thiourea

1-(2',6'-dimethylphenyl)-3-(N-benzylamidino)thiourea

1-(2',6'-dimethylphenyl)-3-(N-methyl-N-benzylamidino)thiourea

1-(2',6'-dipropylphenyl)-3-amidinothiourea

1-(2',6'-difluorophenyl)-3-amidinothiourea

1-(2'-propylphenyl)-3-amidinothiourea

1-(4'-trifluoromethylphenyl)-3-amidinothiourea

1-(2',6'-dimethyl-4'-chlorophenyl)-3-amidinothiourea

1-(2',6'-dimethylphenyl)-3-amidinothiourea

1-(2',6'-diethylphenyl)-3-amidinothiourea

1-(2'-methylphenyl)-3-amidinothiourea

1-(2'-methyl-6'-ethylphenyl)-3-amidinothiourea

1-(2',4',6'-trimethylphenyl)-3-amidinothiourea

1-(2',6'-dimethylphenyl)-3-[N-(2',6'-dimethylphenyl)amidino]thiourea

TABLE IV

1-(2',6'-diethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',6'-diethylphenyl)-4-ethylamino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',6'-diethylphenyl)-4-i-propylamino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',6'-diethylphenyl)-4-pentylamino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',6'-diethylphenyl)-allylamino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',6'-diethylphenyl)-4-propargylamino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',6'-diethylphenyl)-4-cyclopropylamino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',6'-diethylphenyl)-4-methoxyethylamino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',6'-diethylphenyl)-4-benzyloxyethylamino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',6'-diethylphenyl)-4-phenethoxyethylamino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',6'-diethylphenyl)-4-benzylamino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',6'-diethylphenyl)-4-(N,N-dimethylamino)-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',6'-diethylphenyl)-4-(N-pyrrolidinyl)-1,2-dihydro-1,3,5-triazin-2-thione

1-(2'-methyl-6'-ethyl-phenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2'-methyl-6'-ethyl-phenyl)-4-t-butylamino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2'-methyl-6'-ethyl-phenyl)-4-propargylamino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2'-methyl-6'-ethylphenyl)-4-cyclopropylamino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2'-methyl-6'-ethyl-phenyl)-4-cyclopentenyl-3-amino-1,3,5-triazin-2-thione

1-(2'-methyl-6'-ethyl-phenyl)-4-phenethoxyethylamino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2'-methyl-6'-ethyl-phenyl)-4-benzylamino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2'-methyl-6'-ethyl-phenyl)-4-(N,N-diethylamino)-1,2-dihydro-1,3,5-triazin-2-thione

1-(2'-methyl-6'-ethyl-phenyl)-4-[3-(N-methyl-piperidyl)]-1,2-dihydro-1,3,5-triazin-2-thione

1-(2'-methyl-6'-ethylphenyl)-4-(N-morpholinyl)-1,2-dihydro-1,3,5-triazin-2-thione

1-(2'-methyl-6'-chlorophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',6'-dimethyl-4'-acetylamino)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2'-methyl-6'-chloro-4'-acetylamino)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',6'-diethyl-4'-nitrophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',6'-dimethyl-4'-aminophenyl-4-methylamino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',6'-dimethylphenyl)-4-(N,N-diethylamino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',6'-dimethylphenyl)-4-(N,N-dipropylamino)-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',6'-dimethylphenyl)-4-(N-methyl-N-benzyloxyethylamino)-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',6'-dimethylphenyl)-4-(N-pyrrolidinyl)-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',6'-dimethylphenyl)-4-(N,N-dimethylamino)-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',4',6'-trimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',5'-dichlorophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',4',6'-triethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2'-ethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',6'-dimethylphenyl)-4-ethylamino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',6'-dimethylphenyl)-4-propylamino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',6'-dimethylphenyl)-4-(i-propylamino)-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',6'-dimethylphenyl)-4-(t-butylamino)-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',6'-dimethylphenyl)-4-cyclohexylamino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',6'-dimethylphenyl)-4-anilino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',6'-dimethylphenyl)-4-benzylamino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',6'-dimethylphenyl)-4-(N-methyl-N-benzylamino)-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',6'-dipropylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',6'-difluorophenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2'-propylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-thione

1-(4'-trifluoromethylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',6'-dimethyl-4'-chlorophenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',6'-dimethylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',6'-diethylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2'-methylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2'-methyl-6'-ethylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',4',6'-trimethylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-thione

1-(2',6'-dimethylphenyl)-4-(2',6'-dimethylphenylamino)-1,2-dihydro-1,3,5-triazin-2-thione

                  TABLE I-a                                                       ______________________________________                                         ##STR14##                                                                    R.sub.1          R.sub.3      R.sub.4                                         ______________________________________                                         ##STR15##       H            CH.sub.3                                         ##STR16##       CH.sub.3     CH.sub.3                                         ##STR17##       H            OCH.sub.3                                        ##STR18##       H            CH.sub.3                                         ##STR19##       H            CH.sub.3                                         ##STR20##       H            CH.sub.3                                         ##STR21##       H            CH.sub.3                                         ##STR22##       H            CH.sub.3                                         ##STR23##       H            CH.sub.3                                         ##STR24##       H            CH.sub.3                                         ##STR25##       H            H                                                ##STR26##       CH.sub.3     CH.sub.3                                         ##STR27##       H            CH.sub.3                                         ##STR28##       H            C.sub.3 H.sub.7                                  ##STR29##       H            C.sub.2 H.sub.5                                  ##STR30##       H            C.sub.4 H.sub.9                                  ##STR31##       H            CH.sub.3                                         ##STR32##       H            CH.sub.3                                         ##STR33##       H            H                                                ##STR34##       H            CH.sub.3                                         ##STR35##       H            C.sub.2 H.sub.5                                  ##STR36##       CH.sub.3     CH.sub.3                                         ##STR37##       H            OCH.sub.3                                        ##STR38##       H            CH.sub.3                                         ##STR39##       CH.sub.3     CH.sub.3                                         ##STR40##       C.sub.2 H.sub.5                                                                            C.sub.2 H.sub.5                                  ##STR41##       H            H                                                ##STR42##       H            CH.sub.3                                         ##STR43##       H            C.sub.2 H.sub.5                                  ##STR44##       H            OCH.sub.3                                        ##STR45##       CH.sub.3     CH.sub.3                                         ##STR46##       CH.sub.3     C.sub.2 H.sub.5                                  ##STR47##       H            H                                                ##STR48##       H            CH.sub.3                                         ##STR49##       H            C.sub.2 H.sub.5                                  ##STR50##       H            H                                                ##STR51##       H            CH.sub.3                                         ##STR52##       CH.sub.3     CH.sub.3                                         ##STR53##       H            CH.sub.3                                         ##STR54##       H            C.sub.2 H.sub.5                                  ##STR55##       CH.sub.3     CH.sub.3                                         ##STR56##       H            H                                                ##STR57##       H            CH.sub.3                                         ##STR58##       CH.sub.3     CH.sub.3                                         ##STR59##       H            C.sub.2 H.sub.5                                  ##STR60##       H            H                                                ##STR61##       H            CH.sub.3                                         ##STR62##       H            H                                                ##STR63##       H            CH.sub.3                                         ##STR64##       H            C.sub.2 H.sub.5                                  ##STR65##       H            H                                                ##STR66##       H            CH.sub.3                                         ##STR67##       H            CH.sub.3                                         ##STR68##       H            H                                                ##STR69##       H            CH.sub.3                                         ##STR70##       H            C.sub.2 H.sub.5                                  ##STR71##       H            CH.sub.3                                         ##STR72##       CH.sub.3     CH.sub.3                                         ##STR73##       H            CH.sub.3                                         ##STR74##       H            C.sub.2 H.sub.5                                  ##STR75##       H            CH.sub.3                                         ##STR76##       H            CH.sub.3                                         ##STR77##       H            C.sub.2 H.sub.5                                  ##STR78##       H            CH.sub. 3                                        ##STR79##       H            C.sub.2 H.sub.5                                  ##STR80##       H            CH.sub.3                                         ##STR81##       H            C.sub.2 H.sub.5                                  ##STR82##       H            CH.sub.3                                         ##STR83##       H            C.sub.2 H.sub.5                                  ##STR84##       H            CH.sub.3                                         ##STR85##       H            C.sub.2 H.sub.5                                  ##STR86##       H                                                                                           ##STR87##                                       ##STR88##       CH.sub.3                                                                                    ##STR89##                                       ##STR90##       CH.sub.3                                                                                    ##STR91##                                       ##STR92##       CH.sub.3                                                                                    ##STR93##                                       ##STR94##       CH.sub.3                                                                                    ##STR95##                                       ##STR96##       CH.sub.3                                                                                    ##STR97##                                      ______________________________________                                    

                  TABLE I-b                                                       ______________________________________                                         ##STR98##                                                                      R.sub.1                                                                                          ##STR99##                                                ______________________________________                                         ##STR100##                                                                                        ##STR101##                                                ##STR102##                                                                                        ##STR103##                                                ##STR104##                                                                                        ##STR105##                                                ##STR106##                                                                                        ##STR107##                                                ##STR108##                                                                                        ##STR109##                                                ##STR110##                                                                                        ##STR111##                                                ##STR112##                                                                                        ##STR113##                                                ##STR114##                                                                                        ##STR115##                                                ##STR116##                                                                                        ##STR117##                                                ##STR118##                                                                                        ##STR119##                                                ##STR120##                                                                                        ##STR121##                                                ##STR122##                                                                                        ##STR123##                                                ##STR124##                                                                                        ##STR125##                                                ##STR126##                                                                                        ##STR127##                                                ##STR128##                                                                                        ##STR129##                                               ______________________________________                                    

                  TABLE II-a                                                      ______________________________________                                         ##STR130##                                                                   R.sub.1          R.sub.3    R.sub.4                                           ______________________________________                                         ##STR131##      H          CH.sub.3                                           ##STR132##      CH.sub.3   CH.sub.3                                           ##STR133##      H          OCH.sub.3                                          ##STR134##      H          CH.sub.3                                           ##STR135##      H          CH.sub.3                                           ##STR136##      H          CH.sub.3                                           ##STR137##      H          CH.sub.3                                           ##STR138##      H          CH.sub.3                                           ##STR139##      H          CH.sub.3                                           ##STR140##      H          CH.sub.3                                           ##STR141##      H          H                                                  ##STR142##      CH.sub.3   CH.sub.3                                           ##STR143##      H          CH.sub.3                                           ##STR144##      H          C.sub.3 H.sub.7                                    ##STR145##      H          C.sub.2 H.sub.5                                    ##STR146##      H          C.sub.4 H.sub.9                                    ##STR147##      H          CH.sub.3                                           ##STR148##      H          CH.sub.3                                           ##STR149##      H          H                                                  ##STR150##      H          CH.sub.3                                           ##STR151##      H          C.sub.2 H.sub.5                                    ##STR152##      CH.sub.3   CH.sub.3                                           ##STR153##      H          OCH.sub.3                                          ##STR154##      H          CH.sub.3                                           ##STR155##      CH.sub.3   CH.sub.3                                           ##STR156##      C.sub.2 H.sub.5                                                                          C.sub.2 H.sub.5                                    ##STR157##      H          H                                                  ##STR158##      H          CH.sub.3                                           ##STR159##      H          C.sub.2 H.sub.5                                    ##STR160##      H          OCH.sub.3                                          ##STR161##      CH.sub.3   CH.sub.3                                           ##STR162##      CH.sub.3   C.sub.2 H.sub.5                                    ##STR163##      H          H                                                  ##STR164##      H          CH.sub.3                                           ##STR165##      H          C.sub.2 H.sub.5                                    ##STR166##      H          H                                                  ##STR167##      H          CH.sub.3                                           ##STR168##      CH.sub.3   CH.sub.3                                           ##STR169##      H          CH.sub.3                                           ##STR170##      H          C.sub.2 H.sub.5                                    ##STR171##      CH.sub.3   CH.sub.3                                           ##STR172##      H          H                                                  ##STR173##      H          CH.sub.3                                           ##STR174##      CH.sub.3   CH.sub.3                                           ##STR175##      H          C.sub.2 H.sub.5                                    ##STR176##      H          H                                                  ##STR177##      H          CH.sub.3                                           ##STR178##      H          H                                                  ##STR179##      H          CH.sub.3                                           ##STR180##      H          C.sub.2 H.sub.5                                    ##STR181##      H          H                                                  ##STR182##      H          CH.sub.3                                           ##STR183##      H          CH.sub.3                                           ##STR184##      H          H                                                  ##STR185##      H          CH.sub.3                                           ##STR186##      H          C.sub.2 H.sub.5                                    ##STR187##      H          CH.sub.3                                           ##STR188##      CH.sub.3   CH.sub.3                                           ##STR189##      H          CH.sub.3                                           ##STR190##      H          C.sub. 2 H.sub.5                                   ##STR191##      H          CH.sub.3                                           ##STR192##      H          CH.sub.3                                           ##STR193##      H          C.sub.2 H.sub.5                                    ##STR194##      H          CH.sub.3                                           ##STR195##      H          C.sub.2 H.sub.5                                    ##STR196##      H          CH.sub.3                                           ##STR197##      H          C.sub.2 H.sub.5                                    ##STR198##      H          CH.sub.3                                           ##STR199##      H          C.sub.2 H.sub.5                                    ##STR200##      H          CH.sub.3                                           ##STR201##      H          C.sub.2 H.sub.5                                    ##STR202##      H                                                                                         ##STR203##                                        ##STR204##      CH.sub.3                                                                                  ##STR205##                                        ##STR206##      CH.sub.3                                                                                  ##STR207##                                        ##STR208##      CH.sub.3                                                                                  ##STR209##                                        ##STR210##      CH.sub.3                                                                                  ##STR211##                                        ##STR212##      CH.sub.3                                                                                  ##STR213##                                       ______________________________________                                    

                  TABLE II-b                                                      ______________________________________                                         ##STR214##                                                                    R.sub.1             R.sub.10                                                 ______________________________________                                         ##STR215##                                                                                        ##STR216##                                                ##STR217##                                                                                        ##STR218##                                                ##STR219##                                                                                        ##STR220##                                                ##STR221##                                                                                        ##STR222##                                                ##STR223##                                                                                        ##STR224##                                                ##STR225##                                                                                        ##STR226##                                                ##STR227##                                                                                        ##STR228##                                                ##STR229##                                                                                        ##STR230##                                                ##STR231##                                                                                        ##STR232##                                                ##STR233##                                                                                        ##STR234##                                                ##STR235##                                                                                        ##STR236##                                                ##STR237##                                                                                        ##STR238##                                                ##STR239##                                                                                        ##STR240##                                                ##STR241##                                                                                        ##STR242##                                                ##STR243##                                                                                        ##STR244##                                               ______________________________________                                    

                  TABLE III-a                                                     ______________________________________                                         ##STR245##                                                                   ______________________________________                                         R.sub.1        R.sub.3     R.sub.4                                           ______________________________________                                         ##STR246##     H          CH.sub.3                                            ##STR247##     H          CH.sub.3                                            ##STR248##     H          CH.sub.3                                            ##STR249##     H                                                                                         ##STR250##                                         ##STR251##     CH.sub.3                                                                                  ##STR252##                                         ##STR253##     H                                                                                         ##STR254##                                         R.sub.1                                                                                       ##STR255##                                                   ______________________________________                                         ##STR256##                                                                                    ##STR257##                                                    ##STR258##                                                                                    ##STR259##                                                    ##STR260##                                                                                    ##STR261##                                                   ______________________________________                                    

                  TABLE IV                                                        ______________________________________                                         ##STR262##                                                                   ______________________________________                                         R.sub.1        R.sub.3     R.sub.4                                           ______________________________________                                         ##STR263##     H          CH.sub.3                                            ##STR264##     H          CH.sub.3                                            ##STR265##     H          CH.sub.3                                            ##STR266##     H                                                                                         ##STR267##                                         ##STR268##     CH.sub.3                                                                                  ##STR269##                                         ##STR270##     H                                                                                         ##STR271##                                          R.sub.1                                                                                      ##STR272##                                                   ______________________________________                                         ##STR273##                                                                                    ##STR274##                                                    ##STR275##                                                                                    ##STR276##                                                    ##STR277##                                                                                    ##STR278##                                                   ______________________________________                                    

In accordance with the analytical process aspect of this invention, thegas chromatographic separations are carried out in packed columnsprepared according to known methods. Such methods are described forexample in Methods of Biochemical Analysis Vol. II., Ed.; D. Glick,InterScience, New York, 1963.

Generally speaking, the gas chromatographic assay method is carried outby subjecting a sample containing an amidinourea to the derivatizingreaction as disclosed herein and injecting the derivatized sample intothe inlet port of a gas chromatograph of conventional design. Theseparation is readily achieved on either a GSC or GLC column using knownmethods such as described, for example, in Analytical Letters 5 (8) atpage 521, the disclosure of which is hereby incorporated by reference.Suitable fixed phase materials for the GC can be chosen fromcommercially available column packing materials. For quantitativeassays, an internal reference standard is employed to develop acalibration curve. Suitable materials for use as internal referencestandards are, for example, triphenylethylene and tetraphenylethylenewhich give good separations when mixed with amidinourea samples. Thederivatization of an amidinourea containing sample is done in accordancewith the derivatizing method of this invention and is convenientlycarried out on small samples by simply mixing with the derivatizingreagent in a sealed vial, preferably in a suitable solvent such as DMFand assisted by heating.

In addition to their use as derivatives for gas chromatographicanalysis, the 1-aryl-1,2-dihydro-1,3,5-triazin-2-ones and thiones ofthis invention have been shown to possess useful pharmacologicalproperties which can be advantageously used by administering thecompounds to humans for a variety of therapeutic benefits without harm.

1-aryl-1,2-dihydro-2-triazine derivatives are known to possess a broadspectrum of biological activity (Heterocyclic Compounds, Vol. 7, JohnWiley & Sons, Inc., 1961, p. 717-718). The novel compounds of thisinvention constitute a new class of 1-aryl-1,2-dihydro-2-triazines,particularly 1-aryl-1,2-dihydro-1,3,5-triazin-2-ones which similarlyhave a broad spectrum of biological activity. Thus, these compounds havedemonstrated useful gastrointestinal actions and can be used for exampleas antidiarrheal agents for the treatment of gastrointestinal disorders.Whereas amidinoureas also have local anesthetic and otherpharmacological effects when administered at dose levels for effectiveantidiarrheal action, certain of the novel triazinones show goodantidiarrheal activity without local anesthetic or other side effects atactive dose levels. Certain of the novel triazine derivatives have shownother gastrogenic and related effects, particularly antisecretoryaction, making them useful in the treatment of such gastrointestinaldisorders as peptic ulcers. Compounds of this series have also shownanti-motility and spasmolytic effects making them useful in the controlof muscle spasm particularly stomach or intestinal spasms. Certain ofthe compounds have also been found to exhibit novel effects on nerveimpulse transmissions wherein single impulse nerve transmissions areunaffected while multiple high frequency nerve transmissions areblocked.

The amidinoureas from which the novel triazine derivatives are preparedaccording to this invention are known to possess useful pharmacologicalproperties including antidiarrheal activity in mammalian species.Generally, it has been found that the antidiarrheal properties of theamidinourea are not lost in cyclizing to the corresponding triazinederivative. Accordingly, the novel triazine derivatives of thisinvention are also useful antidiarrheal agents as shown by test resultsin animals which, based on pervious experience with the correspondingamidinoureas, show good correlation to activity in humans.

Various tests can be carried out in animal models to show the ability ofthe amidinoureas of this invention to exhibit reactions that can becorrelated with anti-diarrheal activity in humans. The following testsshow the ability of the compounds of this invention to inhibit diarrheain animals and are known to correlate well with antidiarrheal activityin humans. These are considered to be standard tests used to determineantidiarrhea properties. This correlation can be shown by the activitiesof compounds known to be clinically active. In view of results withthese tests, the novel 1,3,5-triazin-2-ones and 1,3,5-triazin-2-thionesof this invention can be considered to be anti-diarrheal agents.

The test compound is dissolved in distilled water, unless otherwisestated. The ED₅₀ values and 95% confidence limits are calculatedaccording to a method described by D. F. Finney (Probit Analysis, 2ndEd., University Press, Cambridge, p. 236, 1964).

1. Antagonism of Castor Oil-induced Diarrhea in Mice

A modified test described by Niemegeers et al. (Arzneim-Forscth 22,516-518, 1972) was used. Groups of ten male Swiss Webster mice (22-25 g)were randomly selected for dosing. Castor oil (Fischer Scientific Co.),0.3 ml/mouse, was given orally one hour after an oral dose of testcompound or the vehicle. After dosing with castor oil, each mouse wasplaced into an individual wire cage and observed for six hours fordiarrhea.

2. Antagonism of Castor Oil-induced Diarrhea in Rats

A test described by Niemegeers et al. (supra) was used. Groups of tenfemale Wistar rats (180-200 g) were randomly selected for dosing. Inaddition, groups of ten female Sprague-Dawly rats (180-200 g) were usedto determine strain difference. Castor oil (Fisher Scientific Co.), 1ml/rat, was given orally one hour after an oral dose of test compound orthe vehicle. After dosing with castor oil, each rat was placed into anindividual wire cage and observed for six hours for diarrhea.

3. Antagonism of Chemically-induced Diarrhea in Mice

Male Swiss Webster mice (18-22 g) in groups of 10-20 mice were randomlyselected for oral dosing with test compound or the vehicle one hourbefore the intraperitoneal injection of either 400 μg/kg of Carbachol(carbamycholine chloride, Sigma Chemical co., St. Louis, Mo.); or, 200μg/kg of serotonin creatinine sulfate (Schwartz/Mann Biochemicals,Orangeburg, N.Y.). After each mouse was injected, it was placed into anindividual wire cage and observed for diarrhea.

4. Inhibition of the Gastrointestinal Transit Time of a Charcoal Meal inMice

A charcoal suspension (10 ml/kg of a 10% suspension) was given orally togroups of ten Swiss Webster male mice (18-22 g) one hour after an oraldose of test compound or vehicle. The mice was sacrificed by cervicaldislocation 30 minutes after the charcoal meal and the distance inmillimeters that the charcoal meal traveled through the small intestinewas measured and compared to the controls. ##EQU1## 5. The Effect ofNaloxone on the Inhibitory Actions of Triazinones on GastrointestinalMotility

Male Swiss Webster mice (18-20 g) in groups of ten were randomlyselected for dosing with test compound or the vehicle alone andconcomitantly with naloxone. The naloxone was dissolved in saline.

The mice were given a charcoal meal (10 ml/kg of a 10% suspension) onehour after an oral does of the vehicle or a test compound(s). Thirtyminutes after the charcoal meal the mice were sacrificed by cervicaldislocation and the distance in millimeters that the charcoal mealtraveled through the small intestine was measured and compared to thecontrols.

6. Fecal Output Tolerance Study in Rats

Male Wistar rats (140-180 g) were given oral doses of either testcompound, diphenoxylate HCl (suspended in methylcellulose or the vehicle(distilled water or methylcellulose) once a day for five consecutivedays. Vehicle or the test compound were given daily 30 minutes beforefecal collection. The feces were collected in a completely automatedfour-tiered metabolic cage over a 12-hour period consisting of three,four-hour intervals. Following collection, the feces were dried for fourhours at 200° C. and weighed.

7. Prostaglandin test

An intraperitoneal injection of 100 micrograms per kilogram of PGE₂causes diarrhea in mice within ten minutes. Groups of mice were orallydosed with test compound at various dose levels after which the PGE₂ isgiven and ten minutes later the mice are checked for diarrhea todetermine the ED₅₀.

Representative compounds of Formula I when subjected to testing inaccordance with the above methods showed antidiarrheal activitycomparable to that of the corresponding amidinoureas.

The results with a representative novel triazinone[1-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride] are as follows.

1. Antagonism of Castor Oil-induced Diarrhea in Mice

An oral dose of 0.3 mls of castor oil caused diarrhea in 20 control micewithin three hours. Test compound, given to ten mice per dose level onehour before an oral dose of castor oil, protected the mice from diarrheain a dose-related way over a period of six hours.

2. Antagonism of Castor Oil-induced Diarrhea in Rats

1-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride protected castor oil treated Wistar and Sprague-Dawleyfemale rats from diarrhea. The compounds have a potency ratio whichcompares favorably with diphenoxylate and loperamide with duration ofaction better sustained.

3. Antagonism of Chemically-induced Diarrhea

Serotonin injected intraperitoneally at 200 μg/kg caused diarrhea in 15control mice within 15 minutes after its injection.1-(2',6-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride given orally to ten mice per dose level protected the micefrom serotonin-induced diarrhea.

An intraperitoneal injection of 400 μg/kg of carbachol caused diarrheain 15 control mice within 20 minutes after its injection.1-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride given orally to five or ten mice per dose level protectedthe mice from carbachol-induced diarrhea.

4. Inhibition of the Gastrointestinal Transit Time of a Charcoal Meal inMice

Twenty mice were used as controls and ten mice at each dose level.Inhibition with1-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride was dose-related.

5. The Effect of Naloxone on the Inhibitory Actions of1-(2,6-dimethylphenyl)-3-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride

Naloxone is a well-known specific antagonist of morphine-like compounds.As previously reported, diphenoxylate was antagonized by naloxonecompetitively in the charcoal meal test. Naloxone had no effect on theactions of1-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride. The dose of naloxone used in this test did not, byitself, change the gastrointestinal transit time of a charcoal meal.

6. Focal Output Tolerance Study in Rats

Groups of rats, five in each group, were given1-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride, 30 mg/kg, and diphenoxylate, 5 mg/kg. for fiveconsecutive days. The triazinone showed no tolerance over the five dayperiod, while diphenoxylate caused a decrease in activity starting onday 2 and continuing through day 5. After 5 days, diphenoxylate had lost72% of its original activity seen on day 1.

7. Antagonism of Prostaglandin E₂ (PGE₂)-induced Diarrhea in Mice

An intraperitoneal injection of 100 μg/kg PGE₃ (Analabs Inc., NorthHaven, Conn.) caused diarrhea in 15 control mice within 15 minutes afterits injection.1-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-trizin-2-onehydrochloride given orally to ten mice per dose level protected the micefrom PGE₃ -induced diarrhea in a dose-related way.

The amidinourea starting materials, in addition to having antidiarrhealproperties, are also known to possess other pharmacological activitiessuch as local anesthetic and cardiovascular activity. Unlike theamidinoureas which generally have local anesthetic properties, thepharmaceutically useful 1-aryl-1,2-dihydro-1,3,5-triazin-2-ones andthiones of this invention have been found to be more specific andsurprisingly effective antidiarrheal doses show little or no classicallocal anesthetic effects nor do they show any significant cardiovasculareffects. The compounds of Formula I are particularly useful asantidiarrheal agents where it is desirable to achieve an antidiarrhealeffect with a minimum of side effects and these compounds are thereforeespecially suited to the treatment of gastrogenic diarrhea. A preferredsubclass of novel triazine derivatives having these properties arerepresented by the formula ##STR279## wherein: R₃ is

hydrogen,

loweralkyl or

loweralkoxy;

R₅ and R₉ are each independently

loweralkyl,

halo,

nitro,

loweralkoxy or

hydroxyloweralkyl.

Compounds where R₅ and R₉ are loweralkyl of 1 to 4 C-atoms areespecially preferred.

The tests employed to determine the separation of local anesthetic andcardiovascular activity at effective antidiarrheal doses withrepresentative compounds of the formula above are as follows:

Several different procedures generally employed in testing for localanesthetic activity are used to determine local anesthetic effects.These tests have been used extensively in the past and have givensatisfactory results in defining the local anesthetic properties ofcompounds.

A discussion of experimental methods for evaluating local anestheticproperties of drugs is found in Evaluation of Drug Activities:Pharmacometrics, Vol. 1, Ed by D. R. Lawrence and A. L. Bacharach,Academic Press, Inc. (London) Ltd. (1964). Applicants herewithincorporate by reference Chapter 9 of this book entitled "LocalAnesthetics", pages 204-214.

Tests which show the lack of side effects of the preferred antidiarrhealtriazinones include the following.

1. Effect on Hexobarbital-induced Loss of Righting Reflex

1-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride and a vehicle given orally 30 minutes before hexobarbitalwere compared for their effect on the duration of the loss of rightingreflex (failure to right within five seconds) induced in groups of SwissWebster mice (10/group, 18-20 g) by the intraperitoneal injection ofhexobarbital (100 mg/kg, l.P.).

2. Effect on Plasma Glucose in Rats

Groups of 5-10 male Sprague-Dawley rats (170-210 g) were orally dosedwith1-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride or the vehicle. Three hours after dosing, the rats weresacrificed by decapitation and blood was collected for plasma glucoseevaluation.

3. Effect on Inducing Emesis on Dogs

Female beagle dogs (6.0-10 kg) were randomly selected for intravenousdosing with1-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride. Each dose of the test compounds was given to either twoor four dogs. Immediately after the injection, the dogs were observedfor emesis for a period of up to one hour.

The results with a representative triazinone are as follows:

1. Effect on Hexobarbital-induced Loss of Righting Reflex

1-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride in doses as great as four times the ED₁₀₀ dose in thecastor oil test in mice, had no effect on the duration ofhexobarbital-induced loss of righting reflex.

2. Effect on Plasma Glucose in Rats

Groups of rats, five per group, were given oral doses of1-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride. A dose-related elevation of plasma glucose resulted.

3. Effect on Inducing Emesis in Dogs

There is a marked difference between1-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride and the corresponding amidinourea in causing emesis inbeagle dogs.1-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride caused no emesis, at doses ten times the dose of theamidinourea within a three minute period following i.v. administration.

Various tests and the results intended to illustrate the effects of thetriazinones on the cardiovascular system are given below.

Cardiovascular Activity of1-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride

Intravenous doses of1-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride at antidiarrheally effective levels did not significantlychange arterial blood pressure, but produced moderate reductions inheart rate. Sympathetically-mediated cardiovascular reflex activity wasonly slightly reduced. Blood pressure responses to challenge doses ofautonomic agonists were not significantly changed.

Antiarrhythmic Effects in Ouabain-intoxicated Dogs

Following ouabain intoxication, one dog received an I.V. infusion of1-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride. After the total dose was infused, the heart rate wasslightly reduced and the blood pressure elevated in association withpartial conversion from ectopic ventricular tachycardia to a primarilynodal rhythm. A second dog received an I.V. infusion of1-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride, at a higher rate. In this dog, heart rate was slightlyreduced and blood pressure was elevated following the infusion, butthere was no conversion from the ouabainintoxicated dogs receiving thecorresponding amidinourea consistently converted to normal sinum rhythmat lower total doses.

Local Anesthetic Effects in Guinea Pigs

Intradermal injections of1-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride as a 0.25% solution were essentially ineffective inprotecting against dermal pain responses. Higher concentration gave someprotection.

An additional test method used to examine the unique local anestheticactivity of the novel triazine compounds of this invention involvesdirect application to the isolated desheathed sciatic-perineal-tibialtrunk of the bullfrog. The methodology used is as follows:

All drug solutions were applied to 15 mm segments of desheathed trunkssituated betwen stimulating and recording electrodes employing astandard pharmacologic technique for observing the conduction blockingeffects of local anesthetics.

Briefly summarized, the technique allows nerve impulses to be initiatedby means of an electrical stimulus applied to a drug-free segment of atrunk and to be conducted through the treated segment. Recordingelectrodes placed on the distal side of the treated segment detect onlythose impulses that were conducted through the 15 mm segment. Byrelating the amplitude of the recorded compound spike potential to thatrecorded before the application of drug treatment, an index is availablefor the proportion of fibers that could conduct impulses through 15 mmof treated length. This index is referred to as "percent of controlspike height" or "percent reduction of spike height" or "percent blockof conduction".

The source of the nerves is the bullfrog, Rana castesbeiana. Duringdissection, the nerves are exposed to Ringer solution having thefollowing composition: 110 mM NaCl, 3.0 mM KCl, 1.8 mM CaCl₂, 20 mMNaHCO₃, 2 mN phosphate buffer. The solution is bubbled with 95% O₂, 5%CO₂ to maintain a pH of 7.2±0.05 at room temperature (22°-24° C.).

Preparation of Ringer solution with test substance:

First, a quantity of drug is weighed out which would make a 50 mMsolution when dissolved in 5.0 ml of Ringer. The drug is dissolved in0.4 ml of absolute ethanol by stirring for 10 minutes at high speed on aGenie Vortex apparatus. The solution is then brought to 5.0 ml withstandard Ringer solution. The drug solution is then diluted 10 timeswith Ringer solution to give a final concentration of 5.0 mM. The finalsolution is bubbled with 95% O₂, 5% CO₂ to give a pH of 7.2. The finalconcentration of ethanol is 0.172 M.

To control for the ethanol in the drug solution, the drug-free Ringersolution used to recover nerves from drug effect was made with the samefinal concentration of ethanol. This ethanol had no effect onconduction.

The same general procedure was used to prepare a solution of the testdrug in a dimethylsulfoxide Ringer solution. The final concentration ofdimethylsulfoxide (DMSO) was 0.101 M. DMSO had no effect on conduction.

Representative compounds of Formula I when tested by this method showedthe following results.

1-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihtdro-1,3,5-triazin-2-onehydrochloride proved to have essentially no conduction blocking actionat a concentration of 5 mM, which is the high end of concentrations usedon desheathed frog trunks with bonafide local anesthetic agents. In 4separate experiments, the average reduction in the A B spike potentialwas only 10%±1.6 (S.E.M.) after 30 minutes contact with the drug. Thisfeeble effect is contrasted with that of 5 mM of the correspondingamidino urea which caused a mean reduction of 77%±8.3 (N=3) within 10minutes of contact; and a total block within 20 minutes in 2 of 3trunks.

This test shows1-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride to be devoid of any important local anesthetic activity onbullfrog peripheral nerves of the A B classification. Accordingly, thisclass of compounds find use in the treatment of diarrhea without causingside effects particularly local anesthesia.

Still another useful subclass of 2-triazine derivatives are those whichpossess unique local nerve/muscles effects. In particular, certain ofthe derivatives have been found to be capable of differentiatedresponses to single impulse and high frequency stimulation in nervetransmission of electrical impulses. Thus, a particular group of novel2-triazine derivatives have been shown to produce complete blocking ofhigh frequency stimulation while permitting complete transmission ofsingle impulse stimulation. Accordingly, these compounds are useful inthose clinical situations where excitable nerve membrane isspontaneously activated at exaggerated rates. Under such conditions,this particular group of novel triazine derivatives can be utilized tolimit the exaggerated rate without limiting the original impulse. Inview of the unique pharmacological effects of certain of these compoundsthey provide an effective tool for use in the study and understanding ofmuscle fiber excitation and nerve impulse transmission. Compounds whichhave been found to be particularly useful for their ability to blockhigh frequency impulse stimulation are compounds of the general formula:##STR280## wherein: R₃ is hydrogen, loweralkyl or loweralkoxy; and

R₅ and R₉ are each separately loweralkyl of 2 to 6 carbon atoms.

The test employed in showing the differentiated local anestheticactivity between single impulse blocking and blocking of high frequencyelectrical stimulation and the results with representative compounds ofthe above formula are given below. The methodology is substantially thesame desheathed nerve test as that described above.

In this test1-(2',6'-diethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride was found to possess weak conduction blocking propertieson isolated bullfrog nerves, but to have a substantial capacity toproduce high frequency failure (h.f.f.).

At a concentration of 5 mM1-(2',6'-diethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride reduces the amplitude of a single compound spike by19%±2.4 in 30 minutes (N=6). This minimal amount of conduction blockwith 5 mM of the triazine is to be contrasted with an 82%±13.4 (N=3)block within 3 minutes with the corresponding amidino urea.

This difference is illustrated by a comparison of the effects andtime-course of 1-(2',6'-diethylphenyl)-4-methylamidinourea (5 mM) withthe corresponding cyclized derivative (5 mM) applied to the left andright trunks from the same animal. The amidinourea at this concentrationcaused a complete block of conduction within 3 minutes; and thetriazinone caused only a minimal block of conduction of single impulses.With continued contact, however, the triazinone produced itscharacteristic h.f.f. which developed slowly but continually.

Recovery from h.f.f. effects of the triazinone were fairly rapid asshown by good recovery in 10 minutes and nearly complete recovery in 30minutes.

Clearly, the triazinone has very weak blocking action, and in relationto the corresponding amidinourea, is virtually inactive in depressingexcitability under widely spaced stimuli. This compound, therefore,reflects a dissociation between simple conduction block and highfrequency failure.

1-(2',6'-diethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride was also compared with lidocaine in 2 trunks. By comparing1(2',6'-diethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride with lidocaine on the same trunk, the experiment wasbiased in favor of the triazinone showing any conduction blockingeffect, yet it showed no block of single impulses at 5 mM, whereaslidocaine showed blockade at 0.75 and 1.0 mM concentrations. Hence,1-(2',6'-diethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride is virtually without conduction blocking action; and isless than 1/5 as active as lidocaine on h.f.f. (The apparently lowpotency of lidocaine in this trunk is most likely due to the use of"winter" frogs whose sensitivity to local anesthetics is reduced incomparison to "summer" frogs.

Since1-(2',6'-diethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride is poorly soluble in Ringer solution, it was dissolvedfirst in either of two solvents, DMSO or ethanol. Nearly all theexperiments were done using ethanol as the initial solvent, but theresults were obtained using the triazinone with 2 different solvents ina pair of trunks from the same animal. Ethanol or DMSO were present intheir respective concentrations in both the triazinone solutions and inthe normal, drug-free Ringer solution used in the recovery of thenerves. The results show that neither of the two solvents wereresponsible for the nerve membrane effects observed.

1-(2',6'-diethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride is virtually without blocking action in nerves stimulatedat a low frequency, i.e., 0.5 Hz, at a concentration of 5 mM. Theaverage reduction in the compound spike of only 20% in 30 minutes standsin marked contrast to the total block within a few minutes by 5 mM1-(2',6'-diethylphenyl)-3-methylamidinourea, its amidinourea precurror.

1-(2',6'-diethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride has a substantial effect on the membrane recoveryprocesses as evidenced by the development of high frequency failure.This phenomenon is associated with the prolongation of the refractoryperiod of the membrane which, in turn, limits the nerve in its abilityto respond to repetitive stimulation at higher frequencies.

In elaborating the above described pharmacological properties of thetriazin-2-ones and triazin-2-thiones of this invention particularly theuseful antidiarrheal properties, it was found that certain of thecompounds show differentiated levels of effectiveness as antisecretoryor antimotility agents when administered in generally used tests inlaboratory animals which tests are known to correlate to humanapplication. The test utilized in establishing the antisecretoryactivity of the triazine derivatives and results with one of thecompounds preferred for use as an antisecretory agent are as follows:

Inhibition of Gastric Acid Secretion in the Rat

The method used has been reported by Shay. Male Sprague-Dawley rats(140-160 g) were fasted 24 hours prior to the test. The rats wereallowed water ad libitum only during the fasting period. One hour beforepyloric ligation the rats (5/group) were given either1-(2',6'-dimethylphenyl-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride, atropine sulfate or the vehicle. The compounds wereprepared in methylcellulose. Pyloric ligation was performed in the ratsunder sodium methohexital anesthesia. Four hours after pyloric ligationthe rats were sacrified by cervical dislocation, the stomachs wereremoved and the gastric contents were assayed for volume, titratableacidity, and tirratable acid output (TAO). A 1 ml aliquot of the gastriccontents was titrated with 0.1N naOH to pH 7.0 for titratable acidity.The percent of inhibition was calculated according to the formula:##EQU2##

The antisecretory effects of compounds of Formula I is shown by theresults with a representative triazinone.1-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride inhibited gastric acid secretion by the Shay rat asfollows: Oral dose mg/kg., 20; No. of rats, 5; Volume, 81;Concentration, 78; Total Acid Output, 96. In contrast to atropine, aspecific anticholinergic drug which caused mydriasis at doses as low as2 mg/kg., 1-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride was devoid of the mydriatic effect at 20 and 16 mg/kg.,respectively.

Compounds of this invention which show antisecretory activity,particularly those in which the antisecretory effects are obtained atdose rates that produce little or no other effects, are especiallyuseful in the treatment of gastrointestinal problems resulting fromabnormal secretory action. A preferred group of compounds for use asdifferentiated antisecretory agents may be represented by the followingformula: ##STR281## wherein: X is oxygen or sulfur (preferably oxygen);

R₃ and R₄ have the same meaning as above; and

R₅ and R₉ are each independently loweralkyl of 2 to 6 carbon atoms; orhalo.

As indicated, the compounds of the above formula suppress acid secretionwith little or no side effects by acting on those parts of mammaliansystems which control gastric secretions thereby aiding in theprevention and alleviation of such disorders as gastritis and ulcers.

Generally speaking, the antidiarrheal compounds of this invention alsoexhibit the ability to suppress gastric motility and among them apreferred group which generally show good anti-motility also have usefulantispasmodic effects making them suitable as spasmolytic agents at doselevels below which any other effects are exhibited. A preferred group ofcompounds for use as spasmolytics are the compounds of the formula:##STR282## wherein: X is oxygen or sulfur (preferably oxygen);

R₃ and R₄ are hydrogen, loweralkyl or loweralkoxy; and

R₅ and R₉ are each loweralkyl, loweralkoxy or halo.

In general, compounds of formula I are indicated for use aspharmacotherapeutic agent in a wide variety of mammalian conditionswhich require relief of symptoms or altering the action of thegastrointestinal or neuro-muscular systems. These compounds when usedfor example, as antidiarrheal, antisecretory or antispasmodic agents,are found to be effective for these purposes when administered orallyand/or parenterally. The term "parenteral" as used herein includesintravenous, intramuscular, intraperatoneal and the like injection orinfusion techniques.

The dosage regimens in carrying out the pharmacotherapeutic methodsutilizing the triazin-2-ones and triazin-2-thiones of this invention arethose which insure maximum therapeutic response until improvement isobtained and thereafter the minimum effective level which gives relief.Thus, in general, the dosages are those that are therapeuticallyeffective in the treatment of diarrhea and related gastrointestinaldisorders. In general, the oral daily dose can be between about 0.1mg/kg and 70 mg/kg (preferably in the range of 0.5-50 mg/kg/day),bearing in mind, of course, that in selecting the appropriate dosage inany specific case, consideration must be given to the patient's weight,general health, age, and other factors which may influence response tothe drug.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents, in order to provide apharmaceutically elegant and palatable preparation. Orally, they may beadministered in tablets, aqueous or oily suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, or syrups orelixers. Tablets which contain the active ingredient in admixture withnon-toxic pharmaceutically acceptable excipients are suitable for themanufacture of tablets. These excipients may be, for example, inertdiluents, for example, calcium carbonate, sodium carbonate, lactose,calcium phosphate or sodium phosphate; granulating and disintegratingagents, for example, maize starch or alginic acid; binding agents, forexample, starch, gelatin or acacia; and lubricating agents, for example,magnesium stearate, stearic acid or talc. The tablets may be uncoated orthey may be coated by known techniques to delay disintegration andabsorption.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with an oilmedium, for example, arachis oil, liquid paraffin or olive oil.

Aqueous solutions containing the active substance and similarcompositions formulated for ease of administration depending upon theparticular therapeutic or prophylatic objective form a separatedevelopment with respect to the active compound disclosed herein.Excipients suitable for aqueous suspensions, may be employed if desired.These excipients are suspending agents, for example, sodiumcarboxymethyl-cellulose, methyl-cellulose, hydroxypropylmethylcellulose,sodium alginate, polyvinylpyrrolidine, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally occurring phosphatide,for example, lecithin; or condensation products of an alkylene oxidewith fatty acids, for example, polyoxyethylene stearate; or condensationproducts of ethylene oxide with long-chain aliphatic alcohols, forexample, heptadecaethyleneoxy-cetanol; or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol, for example, polyoxyethylene sorbitol mono-oleate; orcondensation products of ethylene oxide with partial esters derived fromfatty acids and hexitol anhydrides, for example, polyoxyethylenesorbitan monoleate. The said aqueous suspensions may also contain one ormore preservatives, for example, ethyl, or n-propyl, p-hydroxy benzoate,one or more coloring agents, one or more flavoring agents, and one ormore sweetening agents, such as sucrose.

Oily suspensions may be formulated by suspending the active ingredientin a vegetable oil, for example, arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil, such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example, beeswax, hardparaffin or cetyl alcohol. Sweetening agents, such as those set forthabove, and flavoring agents may be added to provide a palatable oralpreparation. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending or wettingagents and suspending agents are exemplified by those already mentionedabove. Additional excipients, for example, sweetening, flavoring andcoloring agents, may also be present.

The compounds of this invention may also be in the form of oil-in-wateremulsions. The oily phase may be a vegetable oil, for example, olive oilor arachis oils, or a mineral oil, for example, liquid paraffin ormixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example, gum acacia or gum tragacanth,naturally-occurring phosphatides, for example, soya bean lecithin, andesters or partial esters derived from fatty acids and hexitolanhydrides, for example, sorbitan mono-oleage. The emulsions may alsocontain sweeping and flavoring agents.

Syrups and elixirs may be formulated with sweetening agents, forexample, glycerol, sorbitol or sucrose. Such formulations may alsocontain a demulcent, a preservative and flavoring and coloring agents.The pharmaceutical compositions may be in the form of a sterileinjectionable preparation, for example, as a sterile injectable aqueoussuspension. This suspension may be formulated according to the known artusing those suitable dispersing or wetting agents and suspending agentswhich have been mentioned above. The sterile injectable preparation mayalso be a sterile injectable solution or suspension in a nontoxicparenterally-acceptable diluent or solvent, for example, as an aqueoussolution buffered to a pH of 4.0 to 7.0 and made isotonic with sodiumchloride.

Further, the active triazine may be administered alone or in admixturewith other agents having the same or different pharacologicalproperties.

Further, these compounds may be tableted or otherwise formulated fororal use so that for every 100 parts by weight of the composition, thereare present between 5 and 95 parts by weight of the active ingredient.The dosage unit form will generally contain between about 1 mg. andabout 500 mg. of the active ingredients of this invention. The preferredunit dose is between about 10 mg. and about 100 mg. The compositions maybe taken 1-8 times daily depending on the dosage unit required.

Parenteral administration may be carried out using comparative dosagestaken from the oral compositions. In general, the parenteral dosage willbe less than the oral dose and normally within the range of 1/2 to 1/10the oral dose but, of course, this would depend on the absorptioncharacteristics of the compound employed. Dosages would be in thecustomary manner; however, in general, parenteral administration may becarried out neat or the compound may be utilized with a sterile vehicleas mentioned above. Dosage unit forms between 1 mg. and 500 mg. andpreferably in the range of 10 mg. and 100 mg. are useful. The dailyparenteral dose would be between 0.1 mg/Kg/day and 70 mg/Kg/day andpreferably in the range of 0.5 mg/Kg and 50 mg/Kg/day.

The compounds of this invention are also useful as veterinary medicines.In particular, these compounds are useful in the treatment of animalscours, particularly in food animals. When administered in suitableformulations, for example, as additives to food or water, thesecompounds prevent or relieve scours in lambs, calves, piglets and fowls.

EXAMPLE 1

Derivatization of 1-(2',6'-dimethylphenyl)-3-methylamidinourea iscarried out by dissolving about 10 mg. of1-(2',6'-dimethylphenyl)-3-methylamidinourea hydrochloride in 1 ml. ofdimethylformamide and adding 0.1 ml. of dimethylformamide dimethylacetalin a 1 ml. hypo-vial. The vial is sealed with a silicone rubber septum.The mixture is shaken and 2 μl of it is injected into a gaschromatograph (G.C.)

Instrument Conditions:

Column: 6'×4 mm I.D., glass, 10% SE-30 on Chromosorb W (AW-DMCS) H.P.

Oven Temperature: 250° C.

Injection Port Temperature: 270° C.

Detector Temperature: 270° C.

Carrier Gas: N₂, 45 ml/min.

Range: 10³

Recorder Presentation: 100 mv full scale

Injection Volume: 2.0 μl

The best separation of the 1-(2',6'-dimethylphenyl)-3-methylamidinoureaderivative (t_(R) =5.5 min.) from the solvent peak is achieved on anSE-30 column. Tetraphenylethylene (t_(R) =4.7 min.) is chosen as aninternal standard, since it gives a well shaped peak and does notinterfere with other peaks. Triphenylmethane (t_(R) =10.1 min.) may alsobe used as an internal standard.

To evaluate optimum derivatization temperature and time, a samplecontaining 1-(2',6'-dimethylphenyl)-3-methylamidinourea hydrochlorideand triphenylethylene is derivatized and the mixture is injected intoG.C. The peak area ratio of 1-(2',6'-dimethylphenyl)-3-methylamidinoureaderivative to that of the internal standard is followed up to threehours at room temperature. It is found that the derivatization is notcomplete during the period of time. The same experiment at an elevatedtemperature (110° C.) gives complete derivatization within 16 minutes.

Dimethylformamide is chosen as the solvent because it is a relativelygood solvent for both 1-(2',6'-dimethylphenyl)-3-methylamidinoureahydrochloride and triphenylethylene or tetraphenylethylene and has ahigh boiling point (153° C.).

EXAMPLE 2

Derivatized samples are prepared in the following manner. About 10 mg.of the appropriate amidinourea are weighed out and dissolved in a 1 ml.hypo-vial in 1 ml. of DMF. The internal standard (triphenylethylene ortetraphenylethylene) is then added using as much as 1/3 of the sampleweight. 0.1 ml. of dimethylformamide dimethylacetal is added with asyringe. The vial is sealed with a crimper and shaken. The vial isplaced in an oven at about 105°-110° C. for 20 minutes. Analysis is runby injecting 2.0 μl, in duplicate, into the inlet port of the G.C.

To evaluate the response linearity of the G.C. process, mixturescontaining 4.5, 9.0, 13.5, 18.0 and 22.5 mg. of1-(2',6'-dimethylphenyl)-3-methylamidinourea hydrochloride and 3.5 mg.of triphenylethylene are derivatized at 110° C. in an oven for 20minutes and chromatographed. A plot of the peak area ratio of1-(2',6'-dimethylphenyl)-3-methylamidinourea derivative to that of theinternal standard against the concentration of1-(2',6'-dimethylphenyl)-3-methylamidinourea hydrochloride in themixture shows a linear relationship. Mixtures containing below 5 mg.level of 1-(2',6'-dimethylphenyl)-3-methylamidinourea hydrochloride andthe internal standard (0.9, 1.8, 2.7 and 3.6 mg. of1-(2',6'-dimethylphenyl)-3-methylamidinourea hydrochloride and 0.7 mg.of triphenylethylene) also show a linearity. In both cases, however, thelines have negative intercepts indicating that some of1-(2',6'-dimethylphenyl)-3-methylamidinourea derivative is absorbed onthe column. The G.C. method, therefore, should be used with acalibration curve of more than two points.

Instrument Conditions:

Column: 6'×4 mm I.D., glass, 10% SE-30 on Chromosorb W (AW-DMCS) H.P.

Oven Temperature: 250° C.

Injection Port Temperature: 270° C.

Detector Temperature: 270° C.

Carrier Gas: N₂, 45 ml/min.

Range: 10³

Recorder Presentation: 100 mv full scale

Injection Volume: 2.0 μl

Mixtures containing different concentrations of1-(2',6'-dimethylphenyl)-3-methylamidinourea hydrochloride in DMF-DMA,and internal standard when injected into G.C., show the peak area ratioto be linear when plotted against the concentration of1-(2',6'-dimethylphenyl)-3-methylamidinourea hydrochloride. Similarresults are obtained when the method is used for the analysis of1-(2',6'-diethylphenyl)-3-methyl-amidinourea hydrochloride and1-(2',6'-dimethylphenyl)-3-(N,N-dimethyl)-amidinourea. The G.C. methodthus developed shows validity of the assay of1-(2',6'-dimethylphenyl)-3-methylamidinourea hydrochloride and relatedcompounds.

EXAMPLE 3

Isolation and Confirmation of DMF-DMA Derivative of1-(2',6'-dimethylphenyl)-3-methylamidinourea

Derivatization of 1-(2',6'-dimethylphenyl)-3-methylamidinourea iscarried out according to the procedure outlined in Example 2 above. TheDMF-DMA derivative of 1-(2',6'-dimethylphenyl)-3-methylamidinourea isextracted into chloroform leaving the by-product, tetramethylammoniumchloride in aqueous layer. The chloroform solution is evaporated todryness and the resulting product is recrystallized in 2-pentanone.

The pure form of the derivative is subjected to I.R., N.M.R., massspectrometric and elemental analyses to confirm the structure of thederivative.

I.R. Analysis--The I.R. spectrum of the crystallized material fromchloroform shows a singlet at 3300 cm⁻¹ representing--NH stretch ofsecondary amine, a doublet at 1700 cm⁻¹, indicating the presence of--C═N stretches and a strong bond at 1620 cm⁻¹ confirming carbonylfunction from an amide group. However, the spectrum of the materialcrystallized from 2-pentanone is slightly different which indicatesdifferent polymorphic forms of the derivative.

N.M.R. Analysis--The N.M.R. spectrum shows six protons of the two methylgroups on the aromatic ring at 2.20 p.p.m. (singlet), three protons ofthe methyl group (NH--CH₃) at 3.10 p.p.m. (doublet), three protons ofthe aromatic ring at 7.26 p.p.m. (singlet) and one proton (N--CH═N) at7.75 p.p.m. (singlet). The doublet at 3.10 p.p.m. becomes singlet ondeuteration.

Mass Spectrometric Analysis--The chemical ionization mass spectrum ofthis derivative, (GC/MS Finnigan Instrument) is carried out with methaneas a reagent gas. The intense protonated molecular ion (m/e) 231 in thespectrum confirms the molecular weight of the derivative as 230.

Based on the above spectral data, the structure of the DMF-DMAderivative of 1-(2',6'-dimethylphenyl)-3-methylamidinourea is assignedas a 1,2-dihydro-1,3,5-triazine-2-one.

EXAMPLE 4

Preparation of1-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazine-2-one

About 200 mg. of 1-(2',6'-dimethylphenyl)-3-methylamidinourea isintroduced into a gas chromatograph hypo vial and dissolved in 1 ml. ofacetonitrile. To the solution is added 0.2 ml. of DMF DMA reagent. Thevial is sealed with crimper and heated at 105° C. for 15 minutes in anoven. Seven vials are made. The contents of the vials are then put intoa long-neck round bottom flask and evaporated to dryness by a flaskevaporator. The solid mass is dissolved in a mixture of 30 ml. of CH Cl₃and 20 ml. of water and shaken vigorously in a 60 ml. separatory funnel.The aqueous layer is discarded and 20 ml. of water is added and shaken.The CH Cl₃ layer is then taken off and about 10 g. of anhydrous Na₂ SO₄is added, the CH Cl₃ solution is decanted into a flask and evaporated toa dryness. The solid material is dissolved in pentanone-2 (about 80 ml.)at 70° C. The solution is concentrated and crystallizes upon cooling.The crystals are collected and dried in a desiccator with P₂ O₅ withvacuum for one hour.

    ______________________________________                                         Elemental Analysis  MW:230.26  MP:225-226° C.                                   C        H          N                                               ______________________________________                                        Calculated  62.59      6.13       24.33                                       Found       62.84      6.15       24.28                                       ______________________________________                                    

EXAMPLE 5

Preparation of1-(2',6'-diethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-one

The same procedure is followed as in Example 4 above using1-(2',6'-diethylphenyl)-3-methylamidinourea as the starting material andusing as the recrystallization medium a mixed solvent of pentanone andhexane (30:10).

    ______________________________________                                         Elemental Analysis   MP: 210-211° C.                                            C        H          N                                               ______________________________________                                        Calculated  65.09      7.02       21.89                                       Found       65.34      7.01       21.83                                       ______________________________________                                    

EXAMPLE 61-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride

To a suspension of 10.0 g. (39.0 m. mol) of1-(2',6'-dimethylphenyl)-3-methylamidinourea hydrochloride inacrylonitrile (CH₃ CN) (50 ml.) is added 9.3 g. (78.0 m mol) ofdimethylformamide dimethylacetal (DMF-DMA) and the resulting solution,in a bomb, is heated to 100°-105° C. for one hour. After cooling thereaction mixture is placed in a round bottom flask and concentratedunder reduced pressure. The residue is partitioned between H₂ O andCHCl₃ and the layers separated. The aqueous layer is extracted withCHCl₃ (1×50 ml). The combined CHCl₃ extracts are washed with H₂ O (1×50ml) dried (MgSO₄) and concentrated under reduced pressure. A smallamount of the residue is triturated in hexane to give a white solid,having melting point 224. NMR and IR show the product to be identicalwith that of Example 3. The remainder of the residue is dissolved inMeOH and acidified with HCl/MeOH. The MeOH is removed under vacuum andthe residue crystallized from CH₃ CN to give 6.8 g. (65%) of1-(2',60'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride, melting point 234°-8° C. (decomposition).

    ______________________________________                                         Analysis calculated for:  C.sub.12 H.sub.15 ClN.sub.4 O                              C      H         N         Cl                                         ______________________________________                                        Calculated:                                                                             54.04    5.67      21.01   13.29                                    Found:    54.14    5.80      21.90   13.28                                    ______________________________________                                    

EXAMPLE 71-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-dimethylphenyl)-3-methylamidinourea hydrochloride is suspendedin 500 ml. of acrylonitrile in a 1 liter round bottom flask. 95 grams ofDMF-DMA is added. The mixture is heated to reflux with magnetic stirringfor 2 hours then cooled to room temperature. The mixture is concentratedto dryness and the residue precipitated from CH₂ Cl₂ and H₂ O. Theaqueous portion is extracted with 200 ml. of CH₂ Cl₂ and the combinedorganic layers are washed with CH₂ Cl₂ (2×300 ml then with a saturatedNaCl solution and dried over anhydrous MgSO₄ and weighed. The mixture isfiltered to give a white solid which is crystallized from absoluteethanol and recrystallized from CH₂ Cl₂. There is obtained a white solidwhich is dried under vacuum at 80° C. for 4 hours, to give 67.6 grams ofwhite solid having a melting point of 224°-5° C.; NMR confirmed; TLC (3%NH₄ OH/iPA) one spot at R_(f) 0.575 no other point spots; elementalanalysis for C₁₂ H₁₄ N₄ O molecular weight 230.272.

    ______________________________________                                                  C        H          N                                               ______________________________________                                        Calculated  62.59      6.13       24.34                                       Found       62.46      6.32       24.34                                       ______________________________________                                    

The 67.6 grams (0.394 m.) of the product obtained is dissolved in 1liter of iPA 22.8 ml. (0.353 mole) of methane sulfonic acid is added tothe solution with magnetic stirring. After 25 minutes crystals form. Thesolution is cooled to room temperature and filtered. The solid is washedwith iPA and ethanol and dried under vacuum overnight to give themethane sulfonic acid salt of1-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazine-2-one.

EXAMPLE 81-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onemethanesulfonate; Alternative Preparation of Methane Sulfonic Acid Salt

A solution of 6.0 g. (0.026 moles) of1-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazine-2-onein 100 ml. iPA is prepared with warming. To the warm solution is added2.0 ml. (0.031 moles) of methane-sulfonic acid. The mixture becomes hotand crystals of white crystalline solid begin to form almostimmediately. The mixture is allowed to cool to room temperature in tapwater and filtered. The solution is washed with iPA/EtOH and driedovernight at 50°-60° C. in a vacuum to give 8.0 g. of1-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazine-2-onemethanesulfonate.

    ______________________________________                                         Calculated for:  Cl.sub.3 Hl.sub.8 N.sub.4 O.sub.4 S  MW: 326.35 MP:         262-65° C. dec.                                                                C      H         N         S                                          ______________________________________                                        Calculated:                                                                             47.84    5.57      17.17    9.80                                    Found:    48.03    5.71      17.25   10.27                                    ______________________________________                                    

EXAMPLE 91-(2',6'-diethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride

To a suspension of 22.8 g. (80.0 mmol) of1-(2',6'-diethylphenyl)-3-methylamidinourea hydrochloride in CH₂ CN (100ml.) are added 19.1 g. (160.0 mmol) of DMF-DMA and the reaction mixtureis heated at reflux for 3 hours. The CH₃ CN is removed under reducedpressure and the residue partitioned between CHCl₃ and H₂ O. The layersare separated and the aqueous layer extracted with CHCl₃ (1×100). Thecombined CHCl₃ extracts are washed with H₂ O (1×100 ml.), dried (MgSO₄)and concentrated under reduced pressure to give an off-white solid,which by NMR confirms the desired free base. The solution is dissolvedin H₂ OH and acidified with HCl/MeOH and the MeOH removed under reducedpressure to give an off-white solid which is crystallized from CH₃ CN togive after vacuum drying over the weekend (105° C., house vacuum) 16.7g. (71%) of crude product. The material is recrystallized from CH₃ CN (ahot filtration is necessary to remove some undissolved solid) to give11.0 g. (47%) of desired product as a white crystalline solid.

    ______________________________________                                         Analysis calculated for:  C.sub.14 H.sub.18 N.sub.4 OHCl MP:                 208-15° C.                                                                     C      H         N         Cl                                         ______________________________________                                        Calculated:                                                                             57.04    6.50      19.01   12.03                                    Found:    57.14    6.51      19.38   12.01                                    ______________________________________                                    

EXAMPLE 101-(2',6'-dimethylphenyl)-6-methyl-4-methylamino-1,2-dihydro-1,3,5-triazine-2-one

To a suspension of 10.3 g. (40.0 mmol) of1-(2',6'-dimethylphenyl)-3-methylamidinourea hydrochloride in CH₃ CN(50.0 mmol) is added 10.7 g. (80.0 mmol) of N,N-dimethylacetamidedimethylacetal and the resulting mixture heated at reflux for 2-1/2hours. The solvent is removed under vacuum to give a semisolid residuewhich is diluted with H₂ O and the precipitated solid filtered andwashed well with H₂ O then air dried. NMR taken on the crude wet solidshows that the desired product is formed. This solid is recrystallizedfrom CH₃ CN to give 7.8 g. (80%) of product as a white crystallinesolid.

    ______________________________________                                         Analysis calculated for:  C.sub.13 H.sub.16 N.sub.4 ) MP: 251.5°      C. to 252.5° C.                                                                  C        H          N                                               Calculated: 63.91      6.60       22.93                                       Found:      63.52      6.33       23.01                                       ______________________________________                                    

EXAMPLE 114-dimethylamino-1-(2',6'-dimethylphenyl)-1,2-dihydro-1,3,5-triazin-2-onehydrochloride

To a suspension of 19.0 g. (0.07 mole) of1-(2',6'-dimethylphenyl)-3-(N,N-dimethyl)-amidinourea in acrylonitrile(100 m.) is added 16.7 g. (0.14 mole) of DMF-DMA and the mixturerefluxed for 2 hours. The acrylonitrile is removed under reducedpressure and the residue partitioned between H₂ O and CHCl₃. The layersare separated and the aqueous layer extracted with CHCl₃ (1×100 ml.).The CHCl₃ extracts are washed with H₂ O (1×50 ml.), dried over MgSO₄ andconcentrated at reduced pressure to give an oil. Trituration of the oilin EtOH precipitates a white solid which is filtered and washed withEtOH to give the desired product after air drying. The solid isdissolved in MeOH and acidified with HCl/MeOH. The MeOH is removed underreduced pressure to give a white solid which is triturated with CH₃ CN,filtered and washed with CH₃ CN to give 7.5 g. (38%) of product which byNMR seems to be a hydrate or wet. The solid is vacuum dried for 6 hoursat 100° C. under vacuum.

    ______________________________________                                         Analysis calculated for:  Cl.sub.13 H.sub.10 N.sub.4 O . HCl                         C      H         N         Cl                                         ______________________________________                                        Calculated:                                                                             55.61    6.10      19.96   12.63                                    Found:    55.81    5.96      20.31   12.46                                    ______________________________________                                    

EXAMPLE 121-(2-chloro-6-methylphenyl)-4-methylaminodihydro-1,3,5-triazin-2-one

To a suspension of 11.1 g (40 mmol) of1-(2-chloro-6-methylphenyl)-3-methyl amidinourea hydrochloride in 45 mlof CH₃ CN was added 5.7 g (48 mmol) of dimethylformamide dimethylacetalwhich was washed into the flask with an additional 5 ml of CH₃ CN.

The reaction mixture was stirred for 1.5 hours after which an aliquot ofthe reaction product which had been dissolved in MeOH showed there to beone major spot with R_(f) equal to that of1-(2-chloro-6-methylphenyl)-4-methylaminodihydro-1,3,5-triazin-2-one andtwo minor spots of very small R_(f), one at the origin and one of thesame R_(f) as the starting material amidinourea hydrochloride. Thereaction mixture was allowed to stir an additional 0.5 hour and thesolid was filtered to yield1-(2-chloro-6-methylphenyl)-4-methylaminodihydro-1,3,5-triazin-2-one,(EtOAc:MeOH; 9:1). It has the same two impurities as the crude reactionmixture. 7.7 g of the crude mixture was recrystallized from absoluteEtOH; melting point 257.5°-258.5° C.

Most of the1-(2-chloro-6-methylphenyl)-4-methylaminodihydro-1,3,5-triazin-2-one(5.0 g, 65%) was insoluble in hot absolute EtOH. The residue wasfiltered off to yield product having melting point 254°-255.5° C. Theproduct was placed in the vacuum dissicator at 100° C. for 3 hours toyield1-(2-chloro-6-methylphenyl)-4-methylaminodihydro-1,3,5-triazin-2-one,melting point 255.5°-257.5° C.; NMR still showed about 2% CH₃ CNimpurity.1-(2-chloro-6-methylphenyl)-4-methylaminodihydro-1,3,5-triazin-2-one wasreturned to the dissicator at 100° C. for overnight. 4.40 g. of theproduct was dissolved in hot MeOH (100 ml.) and EtOAc was added and thesolution was concentrated on a hot plate until the solution becamecloudy. The solution was allowed to cool to ambient temperature and thenwas placed in the refrigerator. The solid was filtered to yield 0.99 g.,melting point 257.5°-258.5° C.

The filtrate produces a second crop of crystals after sitting overnight.This is filtered to yield an additional 1.41 g. of product with meltingpoint 258° C.

The crystal products are combined and submitted for analysis as1-(2'-chloro-6'-methylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one.

    ______________________________________                                        Analysis calculated for: C.sub.11 H.sub.11 CIN.sub.4 O                                  C      H        N        Cl                                         ______________________________________                                        Calculated: 52.70%   4.42%    22.35% 14.14%                                   Found:      52.61%   4,48%    22.69% 13.89%                                   ______________________________________                                    

IR Analysis (Nujol: 1695, 1655, 1640, 1585, 148, 1465, 1415, 1400, 1375,1305, 1265, 1245, 1225, 1180, 875, 835, 790, 730 and 665 cm.⁻¹.

EXAMPLE 13

To a magnetically stirred suspension of 9.7 g. (40 mmol) of1-(2',6'-dimethylphenyl)amidinourea hydrochloride in 50 ml. of CH₃ CN atroom temperature is added 5.7 g. (48 mmol) of N,N-dimethylformamidedimethylacetal. The reaction mixture is stirred for 10 minutes afterwhich all of the solid material goes into solution. The solution isstirred for 5 minutes after which a seed crystal is added. A white solidprecipitates. The reaction mixture is stirred for an additional 1.5hours, after which the solid precipitate is filtered to yield1-(2',6'-dimethylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one,melting point 248.5°-249.5° C. When recrystallized from absolute EtOHthe product is obtained as a white solid with melting point 258.6°-259°C.

    ______________________________________                                                    C       H         N                                               ______________________________________                                        Calculated:   61.10%    5.59%     25.91%                                      Found:        60.75%    5.76%     25.90%                                      ______________________________________                                    

EXAMPLE 14

To a magnetically stirred suspension of 12.06 g. (38 mmol) of1-N-butoxy-3-(2',6'-dimethylphenyl)amidinourea hydrochloride in 25 ml.of CH₃ CN is added 9.11 g. (76 mmol) of N,N-dimethylformamide dimethylacetal and another 25 ml. of CH₃ CN. All of the solid dissolves afterthe reaction is stirred for 5 minutes. The reaction solution is refluxedfor 2 hours and allowed to come to ambient temperature, thenconcentrated in vacuo to yield the desired product as a white solid.This is combined with 200 ml. of H₂ O to an insoluble, thin gummy solidwhich is transferred to a separatory funnel and extracted with CHCl₃(3×75 ml). The organic layers are combined, washed with H₂ O (2×75 ml)and saturated aqueous brine (1×75 ml). All aqueous washes are combinedand back-extracted with (2×50 ml.), dried (Mg₂ SO₄), filtered andconcentrated in vacuo to yield1-(2',6'-dimethylphenyl)-4-n-butoxyamino-1,2-dihydro-1,3,5-triazin-2-one, as a white solid containing some liquid.The product is triturated with iPA to yield a white solid: m.p.144°-145° C.

    ______________________________________                                        Elemental analysis calculated for: C.sub.15 H.sub.20 N.sub.4                              C       H         N                                               ______________________________________                                        Calculated:   62.48%    6.99%     19.43%                                      Found:        62.49%    6.98%     19.57%                                      ______________________________________                                    

The filtrate is concentrated in vacuo to yield a yellow oil. This oil istriturated with about 20 ml. iPA and a white solid crystallizes out. Thesolid is filtered and washed with cold iPA to yield product with meltingpoint 144°-145.5° C. which appears to be identical to the productobtained above.

EXAMPLE 15

To a magnetically stirred suspension of 15.6 g. (49.5 mmol) of1-(2',6'-dimethylphenyl)-3-sec-butoxyamidinourea hydrochloride in 25 ml.of CH₃ CN is added 11.8 g. (99 mmol) of N,N-dimethylformamidedimethylacetal and another 25 ml. of CH₃ CN. The solid dissolves at thispoint. The reaction solution is heated to reflux. After 2 hours thereaction solution is removed from the heat and allowed to cool toambient temperature transferred to a larger flask and concentrated invacuo.

The white solid residue is taken up in CHCl₃ and washed with H₂ O (3×50ml). All aqueous layers are combined and back-extracted with CHCl₃ (2×50ml). All organic layers are combined and washed with saturated aqueousbrine (1×50 ml). The organic layer is separated, dried (MgSO₄), filteredand concentrated in vacuo to yield only white solid (20.2 g.);impurities from, and possible starting material are present. A smallamount of product is dissolved in boiling Et₂ O, diluted with hexane andconcentrated until solid begins to form. The solid which crystallizesout is1-(2',6'-dimethylphenyl)-4-sec-butoxyamino-1,2-dihydro-1,3,5-triazin-2-one

The entire amount of product is dissolved in boiling Et₂ O, filtered,concentrated in a steam bath, and diluted with hexane until a whitesolid crystallizes out. The solution is cooled to ambient temperature.

The product is filtered and washed with hexane to yield product withmelting point 149° C.

    ______________________________________                                        Analysis calculated for: C.sub.15 H.sub.20 N.sub.4 O.sub.2                                C       H         N                                               ______________________________________                                        Calculated:   62.48%    6.99%     19.43%                                      Found:        62.41%    7.01%     19.27%                                      ______________________________________                                    

EXAMPLE 16 4-Methylamino-1-phenyl-1,2-dihydro-1,3,5-triazin-2-onehydrochloride

To a suspension of 9.5 g. (40.0 mmol) of 1-phenyl-3-methylamidinoureahydrochloride hemihydrate in CH₃ CN (50 ml.) is added 9.5 g. (80.0) ofDMF-DMA and the mixture heated to 105°-110° C. in a closed bomb for 2hours. The reaction mixture is allowed to cool. A solid precipitates.This is filtered and washed with CH₃ Cl. The filtrate is concentratedand the residue diluted with H₂ O. The precipitated solid is filtered,washed with H₂ O and Et₂ O. The two fractions are combined andcrystallized from CH₃ CN. 4.5 g. (56%) of white solid, which by NMRseems to be the hemihydrate, melting point 223°-4° C. is obtained.

    ______________________________________                                        Analysis calculated for: C.sub.10 H.sub.10 N.sub.4 O                                      C        H         N                                              ______________________________________                                        Calculated:   59.40      4.98      27.71                                      Found:        59.27      4.71      28.71                                      ______________________________________                                    

The solid is dissolved (warmed on steam bath) in MeOH and acidified withHCl/MeOH. The MeOH is removed under reduced pressure to give a whitesolid 4-methylamino-1-phenyl-1,2-dihydro-1,3,5-triazin-2-onehydrochloride which is crystallized from CH₃ OH/CH₃ CN.

EXAMPLE 171-(2'-methylphenyl)-4-ethylamino-1,2-dihydro-1,3,5-triazin-2-one

To a magnetically stirred suspension of 9.02 g. (35.2 mmol) of1-(2'-methylphenyl)-3-ethylamidinourea hydrochloride in 30 ml. of CH₃ CNis added 8.40 g. (70.5 mmol) of N,N-dimethylformamide dimethylacetal and20 ml. of CH₃ CN. All of the solid dissolves. The reaction mixture isrefluxed for 2 hours, allowed to come to ambient temperature andpartitioned between CHCl₃ and H₂ O.

The layers are separated and the aqueous layer is extracted with CHCl₃(1×50 ml). The organic layers are combined, washed with H₂ O (1×50 ml)and saturated brine (1×50 ml). These last two aqueous layers arecombined and back-extracted with (1×50 ml.). All organic layers arecombined, dried (MgSO₄), filtered and concentrated in vacuo to yield1-(2'-methylphenyl)-4-ethylamino-1,2-dihydro-1,3,5-triazin-2-one as awhite solid, 8.6 g. (110%). After recrystallizing from EtOAc the productis filtered and dried on the Buckner funnel under vacuum to give thedesired end product with melting point 208.5°-209.5° C.

    ______________________________________                                        Analysis calculated for: C.sub.12 H.sub.14 N.sub.4 O                                      C       H         N                                               ______________________________________                                        Calculated:   62.59%    6.13%     24.33%                                      Found:        62.39%    5.96%     24.64%                                      ______________________________________                                    

EXAMPLE 181-(2',6'-dichlorophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

To a magnetically stirred suspension of 11.88 g. (40 mmol) of1-(2',6'-dichlorophenyl)-3-methylamidinourea hydrochloride in 30 ml. ofCH₃ CN is added 9.52 g. (80 mmol) of N,N-dimethylformamidedimethylacetal in 20 ml. of CH₃ CN. The solid material begins todissolve immediately but in a few minutes, before the starting materialamidinourea has dissolved, another fine particle white solid begins toprecipitate out. The reaction mixture is stirred at ambient temperaturefor 1 hour then heated to reflux for 2 hours. After 2 hours the reactionmixture is allowed to come to ambient temperature and the white solidprecipitate filtered out to yield the desired product, melting point270° C.; TLC (EtoAc 9:1); one major spot, one minor spot at origin. Asmall sample recrystallized from CH₃ OH/EtoAc gave 1 spot on TLC. (9.6g. 89%). The product is recrystallized from MeOH to yield1-(2',6'-dichlorophenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one.

The recrystallizing solution is concentrated from 1400 ml. to 700 ml.,then refrigerated after a lot of solid comes out. After refrigerationfor several hours, the solid is filtered and washed with cold MeOH toyield additional product having melting point 270° C. TLC (EtOAc/MeOH;9:1) still shows a very small spot at origin.

    ______________________________________                                        Analysis calculated for: C.sub.10 H.sub.8 N.sub.4 Cl.sub.2 O                            C      H        N        Cl                                         ______________________________________                                        Calculated: 44.30%   2.97%    20.67% 26.16%                                   Found:      44.24%   2.73%    20.80% 26.09%                                   ______________________________________                                    

EXAMPLE 191-(2'-methylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

To a magnetically stirred suspension of 9.72 g. (40 mmol) of1-(2'-methylphenyl)-3-methylamidinourea hydrochloride in 30 ml. of CH₃CN is added 9.52 g. (80 ml.) of N,N-dimethylformamide dimethylacetal.After the mixture is further diluted with 25 ml. CH₃ CN and stirred for5 minutes all of the solid is dissolved. TLC (3% NH₄ OH) shows a newspot; about equal in size to a spot in starting material; (EtoAc/MeOH;9:1) shows mostly a new spot. The solution is refluxed for 2 hours. Thereaction mixture is allowed to cool to ambient temperature. The reactionmixture is then poured into CHCl₃ /H₂ O and separated. The aqueous layeris extracted with CHCl₃ (for a total of 3×50 ml.). The organic layersare combined and washed with H₂ O (2×50 ml.). The aqueous layers arecombined and back extracted with CHCl₃ (1×50 ml.). All organic layersare combined, dried, filtered and concentrated in vacuo to yield theproduct which is recrystallized from absolute EtOH, filtered and washedwith cold absolute EtOH and air-dried. The product is1-(2'-methylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one,melting point 191.5°-192.5° C.

    ______________________________________                                        Analysis calculated for: C.sub.11 H.sub.12 N.sub.4 O                                   C        H          N                                                ______________________________________                                        Calculated:                                                                              61.10%     5.59%      25.91%                                       Found:     61.02%     5.80%      26.25%                                       ______________________________________                                    

EXAMPLE 201-(2',6'-dimethylphenyl)-4-(2,2,2-trifluoroethylamino)-1,2-dihydro-1,3,5-triazin-2-one

To a suspension of 130 g. (40.0 mmol) of1-(2',6'-dimethylphenylcarbamoyl-3-(2,2,2-trifluoroethyl) guanidinehydrochloride in CH₃ CN (50 ml.) is added 95 g. (80.0 mmol) of DMF-DMAand the mixture heated at reflux for 2 hours. The solvent is removedunder vacuum and the residue partitioned between CHCl₃ and H₂ O. Thelayers are separated and the aqueous layer is extracted with CHCl₃(1×100 ml.). The extracts are dried (MgSO₄) and concentrated to give awhite solid which is crystallized from absolute EtOH to give afterheating under vacuum at 100° C. for 1 hour; 9.5 g. (80%) of1-(2',6'-dimethylphenyl)-4-(2,2,2-trifluoroethylamino)-1,2-dihydro-1,3,5-triazin-2-one;melting point 212.3° C.

    ______________________________________                                        Analysis calculated for: C.sub.13 H.sub.13 F.sub.3 N.sub.4 O                          C       H         N         F                                         ______________________________________                                        Calculated:                                                                             52.35     4.39      18.78   19.11                                   Found:    52.45     4.31      19.67   18.84                                   ______________________________________                                    

EXAMPLE 21 1-(2-pyridyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

A 14.0 g. (72.5 mmol) of 1-(2-pyridyl)-3-methylamidinourea is placed in100 ml. of MeOH and heated slightly. The solid does not dissolve. A 50ml. portion of an HCl/MeOH solution is added such that the solutionbecomes acid. Most of the solid dissolves. An additional 100 ml. of MeOHis added; some more solid dissolves but not all, even upon heating. Anadditional 50 ml. of MeOH is added. All of the solid dissolves. Thissolution is concentrated to 1/2 volume (150 ml.) on a hot plate and CH₃CN is added to it, with additional concentration until the hot solutionbecomes cloudy. The solution is allowed to cool to ambient temperature.

The solid is filtered to yield the product with melting point153.5°-157° C. which after air-drying for 3 hours has melting point156°-159° C. and after drying in a vacuum desiccator has melting point155.5°-158° C.

To a magnetically stirred suspension of 14.50 g. (54.5 mmol) of1-(2-pyridyl)-3-methylamidinourea dihydrochloride in 50 ml. of CH₃ CNthere is added 15 ml. (13.46 g. 113 mmol) of N,N-dimethylformamidedimethylacetal. Some of the solid appears to dissolve butreprecipitation occurs within seconds. The reaction mixture is warmed. ATLC (iPA:NH₄ 3:1) shows no starting material present after 5 minutes.

The reaction mixture is stirred for 2 hours and filtered to yieldproduct of melting point 117.5°-190° C.; 8.5 g. (77%); TLC (iPA-NH₄ OH);shows a minor spot with same R_(f) as starting material and a major spotwith R_(f) about twice as large.

The product is dissolved (mostly) in hot MeOH, hot filtered andconcentrated in a hot plate to 350 ml. and allowed to come to ambienttemperature overnight.

The next morning a precipitate of white crystals has formed. Thesolution is cooled to the refrigerator. This cooled solution is filteredand washed with MeOH to yield product with melting point 240.5°-242° C.;TLC (iPA:NH₄ OH); (Et₂ O), (EtOAc:MeOH; 9:1): shows only one spot in allsolvent systems.

    ______________________________________                                        Elemental analysis calculated for: C.sub.9 H.sub.9 N.sub.5                             C        H          N                                                ______________________________________                                        Calculated:                                                                              53.20%     4.46%      34.46%                                       Found:     53.11%     4.46%      35.42%                                       ______________________________________                                    

EXAMPLE 221-(2'-bromo-6'-methylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one

To a suspension of 5.5 g. (0.017 moles) of1-(2'-bromo-6'-methylphenyl)-3-methyl-amidinourea in 60 ml. of CH₃ CNthere is added 5.3 ml. (about 0.07 moles) of dimethyl formamide-dimethylacetal. Solid begins to dissolve and a new solid precipitates. Themixture is heated to reflux and kept there for 2 hours. The solutionremains clear on cooling to room temperature. The CH₃ CN is removed invacuo and the resulting thick oil stirred in 80 ml. of H₂ O. Theresulting solid is removed by filtration and washed with H₂ O (about 100ml.).

The solid after air drying is recrystallized from THF (200 ml.) heatedand boiled down to about 50 ml. After cooling, filtration, and washingwith hexane there is obtained 3.0 g. of1-(2'-bromo-6'-methylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onemelting point 238°-40° C. Analysis indicates very pure material but asecond crop of off-white crystals about 2.0 g. is not as pure. Thematerials are combined and dissolved in hot iPA, filtered and 1.5 ml.(about 0.023 moles) of CH₃ SO₃ H is added. The mixture is cooled. Theresultant solid is removed by filtration and washed with EtOAc. Thesolid is recrystallized from CH₃ OH/EtOAc to give 5.20 g. of crystallineproduct, melting point 243°-6° C. (with decomposition).

    ______________________________________                                        Calculated for: C.sub.12 H.sub.15 BrN.sub.4 O.sub.4 A                                            MW: 391.23                                                        C      H        N        Br     S                                      ______________________________________                                        Calculated:                                                                            36.84    3.87     14.32  20.43  8.18                                 Found:   37.00    3.96     14.30  20.49  8.4                                  ______________________________________                                    

EXAMPLE 231-(2',6'-dimethylphenyl)-4-[(2-pyridyl)methylamino]-1,2-dihydro-1,3,5-triazin-2-one

To a suspension of 10.2 g. (28.0 mmol) of1-(2',6'-dimethylphenyl)-3-[(2-pyridyl)methyl]amidinourea in CH₃ CN (100ml) is added 10.0 g. (84.0 mmol) of DMF-DMA and the reaction mixtureheated at reflux for two hours. The solvent is removed under vacuum andthe residue diluted with H₂ O and made basic with 10% aqueous NaOH (pH10). The aqueous layer is extracted with CHCl₃ (2×100 ml.) and theextracts dried (MgSO₄) and concentrated under vacuum to an orange oil,which by NMR looks to be a mixture of starting material and product. Theoil is layered out with H₂ O and Et₂ O. The oil solidifies. This solidis filtered and washed with H₂ O and Et₂ O and air dried. The solid isthen crystallized (2×) from EtoAc to give 3.2 g. (37%) of a tancrystalline solid, melting point 165°-6° C.

    ______________________________________                                        Analysis calculated for: C.sub.17 H.sub.17 N.sub.5 O                                    C        H          N                                               ______________________________________                                        Calculated: 66.43      5.58       22.79                                       Found:      66.51      5.36       22.89                                       ______________________________________                                    

EXAMPLE 241-(2',6'-dimethylphenyl)-4-methoxyamino-1,2-dihydro-1,3,5-triazin-2-onehydrate

To a suspension of 10.9 g. (40.0 mmol) of1-(2',6'-dimethylphenyl)-3-methoxyamidinourea in CH₃ CN (50 ml.) isadded 9.5 g. (80.0 mmol) of DMF-DMA and the mixture heated at 105°-110°C. in a closed bomb for 11/2 hours. The reaction mixture is cooled andpoured into a round bottom flask and the CH₃ CN removed under reducedpressure. The residue is partitioned between CHCl₃ and H₂ O and thelayer separated. The aqueous layer is extracted with CHCl₃ (1×75 ml.).The combined organic layers are washed with H₂ O (1×50 ml.), dried(MgSO₄) and concentrated under reduced pressure to give an oily residue.The residue is taken up in Et₂ O and washed with H₂ O (2×50 ml.). TheEt₂ O layer is dried (MgSO₄) and concentrated under reduced pressure togive a viscous oil. NMR shows that DMF has been removed. The oil istaken up in hot CH₃ CN cooled and a small amount of CHCl₃, H₂ O and DMSOinsoluble material filtered off. The filtrate is concentrated to give aviscous oil. TLC of the oil (Silicagel; 3% NH₄ OH, iPA) versus startingmaterial shows one spot moves slower than starting material. Uponaddition of MeOH and warming on a steam bath the oil solidifies. Thesolid is crystallized from MeOH to give 4.6 g. (43%) of1-(2',6'-dimethylphenyl)-4-methoxyamino-1,2-dihydro-1,3,5-triazin-2-oneas a white solid, melting point 78°-80° C.

    ______________________________________                                        Analysis calculated for: C.sub.12 H.sub.14 N.sub.4 O.sub.2                              C        H          N                                               ______________________________________                                        Calculated: 58.53      5.73       22.75                                       Found:      55.04      6.20       21.48                                       ______________________________________                                    

The NMR shows a broad peak at 3.58 which is integrated for two protons.This peak disappeared on adding D₂ O. The analysis recalculated for thepresumed hydrate is as follows:

    ______________________________________                                        Analysis calculated for: C.sub.12 H.sub.16 N.sub.4 O                                    C        H          N                                               ______________________________________                                        Calculated: 54.54      6.10       21.20                                       Found:      55.04      6.20       21.48                                       ______________________________________                                    

Analysis indicates compound is obtained as the hydrate.

EXAMPLE 251-(2',6'-Dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onemethanesulfonate

To 29.2 grams (0.4 mole) of N,N-dimethylformamide, heated to 50°-60° C.,are added dropwise 50.5 grams (0.4 mole) of dimethyl sulfate whilemaintaining the temperature between 50° and 60° C. After the addition,the reaction mixture is heated at 70°-80° C. for four hours. Thereaction mixture is diluted with acetonitrile (150 milliliters) andcooled to approximately 10° C. in an ice water bath. Then 44.0 grams(0.2 mole) of 1-(2',6'-dimethylphenyl)-3-methylamidinourea are added onone portion followed by the dropwise addition of 80.8 grams (0.8 mole)of triethylamine while keeping the temperature below 25° C. The reactionmixture is allowed to come to ambient temperature and stirred for onehour. The solvent is removed in vacuo and the residue diluted with waterand the pH adjusted to 10 with ten percent (10%) aqueous sodiumhydroxide. The aqueous layer is extracted with chloroform (3 times with200 milliliters each time) and the combined extracts dried (MgSO₄) andconcentrated in vacuo. The residual solid is taken up in boilingacetonitrile (350 milliliters) and concentrated to approximatelytwo-thirds of its volume on a steam bath. The hot solution is treatedwith 21.0 grams (0.22 mole) of methanesulfonic acid and on cooling awhite crystalline solid deposits, which is filtered, washed with coldacetonitrile and vacuum dried at 80° C. for one hour at yield 60.6 grams(93%) of1-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onemethanesulfonate, m.p. 264°-266° C. dec.

EXAMPLE 261-(2',6'-Diethylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one

To a magnetically stirred suspension of 23.4 g (0.10 mol.) of1-(2',6'-diethylphenyl) amidinourea in 100 ml of CH₃ CN is added 23 g(0.20 mol.) of N,N-dimethylformamide dimethylacetal. The reaction isstirred at ambient temperature and monitored by Tlc. After two hours thesolid has all dissolved.

After 2.5 hours the reaction mixture is concentrated in vacuo to yield agreenish oil. The oil is taken up in CHCl₃ and let stand overnight, thenwashed with H₂ O(3×50 ml) and saturated aqueous brine (2×50 ml). Allaqueous layers are combined and back-extracted with CHCl₃ (2×25 ml). Allorganic layers are combined, dried (Na₂ SO₄), filtered and the filtrateconcentrated in vacuo. The residue is triturated with hot EtOAc andfiltered. The filtrate is combined with Et₂ O and a solid precipitatesout. The solid is filtered to yield(2',6'-diethylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one calculatedfor C₁₃ H₁₆ N₄ O.

Calculated: 63.92%C; 6.60%H; 22.93%N. Found: 63.88%C; 6.77%H; 22.78%N.

The product is recrystallized from EtOAc, refrigerated, filtered andwashed with cold EtOAc, triturated with Et₂ O and filtered to yield awhite solid, which is recrystallized from EtoAc to give1-(2',6'-diethylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one; m.p.136.5°-138.5° C.

EXAMPLE 27 1-(2',6'-diethylphenyl)-4-dimethylaminomethyleneamino-1,2-dihydro-1,3,5-triazin-2-one

1-(2',6'-diethylphenyl)-4-amino-1,2-dihydro-1,3,5-triazin-2-one (5.9 g,20 mmo) is combined with 30 ml of CH₃ CN, none of the solid dissolves.To this is added 1.19 g (10 mmol) of N,N-dimethylformamidedimethylacetal. The solid dissolves within seconds. The reactionsolution was stirred overnight.

After the reaction solution is stirred overnight, it darkens to a lightbrown color. Tlc does not appear to show any starting material stillpresent. The reaction mixture is concentrated in vacuo to yield alight-brown solid which is taken up in CHcl₃, washed with H₂ O (3×35 ml)and saturated aqueous brine (2×50 ml). All aqueous washes are combinedand back-extracted with CHCl₃ (2×50 ml). All organic layers arecombined, dried (Na₂ SO₄), filtered and filtrate concentrated in vacuoto yield an oil which looks like pure compound with no startingmaterial. The oil solidifies and is recrystallized from EtoAc.

The solid is filtered and washed with cold EtOAc: m.p. 144°-146° C.calculated for C₁₆ H₂₁ N₅ O.

Calculated: 64.19%C; 7.07%H; 23.29%N. Found: 64.11%C; 7.24%H; 23.59%N.

EXAMPLE 281-(2',6'-Diethylphenyl-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride

To a suspension of 22.8 g (80.0 mmol) of1-(2',6'-diethylphenyl-4-methylamino-1,2-dihydro-1,3,5-one in CH₃C.tbd.N (100 ml) is added 1911 g (160.0 mmol) of DMF-DMA and thereaction mixture heated at reflux for 3 hours. The CH₃ C.tbd.N isremoved under reduced pressure and the residue partitioned between CHCl₃and H₂ O). The layers are separated and the aqueous layer extracted withCHCl₃ (1×100 ml). The combined CHCl₃ extracts are washed with H₂ O(1×100 ml), dried (MgSo₄) and concentrated under reduced pressure togive an off-white solid, which by NMR confirms the desired free base.The solid is dissolved in the OH and acidified with HCl/MeOH and theMeOH removed under reduced pressure to give an off-white solid which iscrystallized from CH₃ C.tbd.N to give after vacuum drying over theweekend, 16.7 grams of1-(2',6'-diethylphenyl-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride; m.p. 213-215.

EXAMPLE 291-(2',6'-diethylphenyl)-4-ethylamidino-1,2-dihydro-1,3,5-triazin-2-one

To a magnetically stirred stined suspension of 10/5 g (40 mmol) of1-(2',6'-diethylphenyl)-3-ethylamidinourea in 10 ml of CH₃ CN is added9.52 g (80 mmol) of N,N-dimethylformamide dimethylacetal and another 20ml of CH₃ CN. The reaction mixture is heated to reflux at which pointall of the solid dissolves. The solution is refluxed for one hour,allowed to cool to ambient temperature and then concentrated in vacuo toyield an off-white solid which is taken up in CHCl₃, washed with H₂ O)(2×50 ml) and saturated aqueous brine (2×25 ml). All aqueous wash layersare combined and back-extracted with CHCl₃, (2×25 ml). All organiclayers are combined, dried (Na₂ SO₂), filtered and the filtrateconcentrated in vacuo to yield a yellow oil. The oil is taken up in MeOHand acidified with HCl/MeOH then concentrated in vacuo.

The off-white solid which resulted is recrystallized from EtoAc/MeOH toyield 1-(2,6-diethylphenyl)-4-ethylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride; m.p. 200°-205° C. M.P. 200.5°-204.5° C. SOC-1103-76Banalysis (calculated for C₁₅ H₂₁ ClN₄ O).

Calculated: 58.34%C; 6.86%H; 18.14N; 11.48%Cl. Found: 56.44%C; 6.86%H;17.72%N; 12.29%Cl.

EXAMPLE 301-(2',6'-diethylphenyl)-4-n-propylamino-1,2-dihydro-1,3,5-triazin-2-oneHCl

To a magnetically stirred suspension of 11.04 g (40 mmol) of1-(2',6'-ethylphenyl)-3-n-propylamidinourea in 20 ml of CH₃ CN is added9.52 g (80 mmol) of N,N-dimethylformamide dimethylacetal and anadditional 20 ml of CH₃ CN. The solid dissolves but not entirely,perhaps due to formation of new solid. The reactant mixture is heated toreflux and the solid dissolved. After the solution is refluxed for 0.5hours, the solution is allowed to cool to ambient temperature andstirred overnight. The next morning a solid has appeared.

The reaction mixture is concentrated in vacuo to yield an off-whitesolid which is taken up in CHCl₃, washed with H₂ O (3×50 ml) andsaturated aqueous brine (2×50 ml). All aqueous wash layers are combinedand back-extracted with CHCl₃. All organic layers are combined, dried(Na₂ SO₄), filtered and the filtrate concentrated in vacuo to yield anoff-white solid which is dissolved in MeOH, acidified with HCl/MeOH andconcentrated in vacuo to give1-(2',6'-diethylphenyl)-4-n-propylamino-1,2-dihydro-1,3,5-triazin-2-one.HCl.

Analysis calculated for C₁₆ H₂₃ ClN₄ O: Calculated: 59.53%C; 7.18%H;10.98%Cl; 17.35%N. Found: 59.04%C; 7.35%H; 11.29%Cl; 17.37%N.

EXAMPLE 314-n-Butylamino-1-(2',6'-diethylphenyl)-1,2-dihydro-1,3,5-triazin-2-one

To a solution of 8.7 g (0.03 mol) of3-n-butylamidino-1-(2',6'-dimethylphenyl)-urea in CH₃ C═N(50 ml) areadded 7.2 g (0.06 mol) of DMF-DMA and the mixture is refluxed for 2hours. The solvent is removed under vacuum to give a solid residue whichis dissolved in MeOH (warm) and acidified with HCl/MeOH. The MeOH isremoved under vacuum to give an oil.

This oil is dissolved in EtoAc. The EtoAc is removed under vacuum andthe residue dissolved in CH₂ Cl₂ and washed with 10% aqueous NaoH (1×50ml). The aqueous layer is extracted with CH₂ CL₂ (6×75 ml) and the CH₂Cl₂ extracted, combined, dried (MgSO₄) and concentrated under reducedpressure to a solid which is crystallized from EtoAc to give 5.5 g of4-n-butylamino-1-(2',6'-diethylphenyl)-1,2-dihydro-1,3,5-triazin-2-oneas a white solid, m.p. 178°-9° C.

We claim:
 1. A compound of the formula ##STR283## wherein: X is oxygenor sulfur;R₁ is aryl, aryl lower alkyl, a 5 or 6 membered heterocycle ora lower alkyl substituted 5 or 6 membered heterocycle; R₂ is hydrogen orlower alkyl; and R₃ and R₄ are each independently selected from thegroup consisting of hydrogen, hydroxyl, lower alkanoyl, lower alkyl,cyclo-lower alkyl, lower alkenyl, lower alkynyl, halo-lower alkyl, loweralkoxy-lower alkyl, hydroxy-lower alkyl, phenoxy-lower alkyl,diloweralkyl amino, aryl or aryl-lower alkyl, lower alkoxy, phenoxy, a 5or 6 membered heterocycle or a lower alkyl substituted 5 or 6 memberedheterocycle or R₃ and R₄ together with the nitrogen to which they areattached form a 3 to 7 membered heterocyclic ring, selected from thegroup consisting of oxazolidinyl, thiazolidinyl, pyrazolidinyl,imidazolidinyl, piperidyl, piperazinyl, thiamorpholinyl,trimethylenetriaminyl, ethyleneiminyl, and morpholinyl;and, wherein:aryl means phenyl or phenyl in which one or more of the phenyl hydrogenshas been replaced by the same or different substituents selected fromthe group consisting of halo, lower alkyl, halo-lower alkyl, nitro,amino, lower alkylacylamino, hydroxy, lower alkoxy, phenyl-lower alkoxy,lower alkyl acyloxy, cyano, halo-lower alkoxy or lower alkyl sulfonyl;and, 5 or 6 membered heterocycle means a heterocyclic substituentselected from the group consisting of pyridyl, pyrimidyl, pyrazolyl,imidazolyl, furyl, thienyl, oxazolyl, thiazolyl, piperidyl, andmorpholinyl; and the non-toxic pharmaceutically acceptable saltsthereof.
 2. A compound according to claim 1 wherein X is oxygen.
 3. Acompound of the formula ##STR284## wherein X is oxygen or sulfur; R₁ isphenyl, benzyl or phenethyl; or phenyl, benzyl or phenethyl in which oneor more of the phenyl hydrogens are substituted by lower alkyl, loweralkoxy, halo, halo-lower alkyl, amino, nitro, lower alkyl acyloxy, loweralkyl acylamino, hydroxy, cyano, carboxyl, or lower alkyl sulfonyl;pyridyl or pyridyl in which one or more of the hydrogens are substitutedby lower alkyl, lower alkoxy, halo, halo-lower alkyl, amino, nitro,lower alkyl acyloxy, lower alkyl acylamino, hydroxy, cyano, carboxyl, orlower alkyl sulfonyl; R₂ is hydrogen or lower alkyl, and R₃ and R₄ areeach independently selected from the group consisting of hydrogen,hydroxyl, lower alkanoyl, lower alkyl, lower alkenyl, lower alkynyl,lower alkoxy, halo-lower alkyl, hydroxy-lower alkyl, lower alkoxy-loweralkyl, phenoxy-lower alkyl, di-lower alkyl-amino-lower alkyl or R₃ andR₄ together with the nitrogen to which they are attached form a 5 or 6membered nitrogen heterocycle selected from the group consisting ofoxazolidinyl, thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidyl,piperazinyl, thiamorpholinyl, and morpholinyl; and the pharmaceuticallyacceptable non-toxic salts thereof.
 4. A compound according to claim 3wherein X is oxygen.
 5. A compound of the formula ##STR285## wherein Xis oxygen or sulfur; R₁ is phenyl, pyridyl, phenyl in which one or moreof the phenyl hydrogens is replaced by lower alkyl, lower alkoxy, halo,halo-lower alkyl, amino, nitro, lower alkyl acyloxy, lower alkylacylamino, hydroxy, cyano, carboxyl, or lower alkyl sulfonyl, or pyridylin which one or more of the hydrogens is replaced by lower alkyl, loweralkoxy, halo, halo-lower alkyl, amino, nitro, lower alkyl acyloxy, loweralkyl acylamino, hydroxy, cyano, carboxyl, or lower alkyl sulfonyl; R₂is hydrogen or lower alkyl, and R₃ and R₄ are each independentlyselected from the group consisting of hydrogen, hydroxyl, loweralkanoyl, lower alkyl, lower alkenyl, lower alkynyl, lower alkoxy,halo-lower alkyl, hydroxy lower alkyl, lower alkoxy lower alkyl, phenoxylower alkyl, di-lower alkyl-amino lower alkyl or R₃ and R₄ together withthe nitrogen to which they are attached form a 5 or 6 membered nitrogenheterocycle selected from the group consisting of oxazolidinyl,thiazolidinyl, pyrazolidinyl, imidazolidinyl, piperidyl, piperazinyl,thiamorpholinyl, and morpholinyl; and the pharmaceutically acceptablenon-toxic salts thereof.
 6. A compound according to claim 5 wherein X isoxygen.
 7. A compound of the formula ##STR286## wherein: X is oxygen orsulfur;R₂ is hydrogen or lower alkyl; R₃ and R₄ are each independentlyselected from the group consisting of hydrogen, hydroxyl, loweralkanoyl, lower alkyl, cyclo-lower alkyl, lower alkenyl, lower alkynyl,halo-lower alkyl, lower alkoxy-lower alkyl, hydroxy-lower alkyl,phenoxy-lower alkyl, diloweralkylamino, aryl or aryl-lower alkyl, loweralkoxy, phenoxy and 5 or 6 membered heterocycles selected from the groupconsisting of pyridyl, pyrimidyl, pyrazolyl, imidazolyl, furyl, thienyl,oxazolyl, piperidyl and morpholinyl, or R₃ and R₄ together with thenitrogen to which they are attached form a 3 to 7 membered ring selectedfrom the group consisting of oxazolidinyl, thiazolidinyl, pyrazolidinyl,imidazolidinyl, piperidyl, piperazinyl, thiamorpholinyl,trimethylenetriaminyl, ethyleneiminyl, and morpholinyl; and R₅, R₆, R₇,R₈ and R₉ are each independently selected from the group consisting ofhydrogen, lower alkyl, lower alkoxy, halo, halo-lower alkyl, amino,nitro, lower alkyl acyloxy, lower alkyl acylamino, hydroxy, cyano,carboxyl, or lower alkyl sulfonyl;and, wherein: aryl means phenyl orphenyl in which one or more of the phenyl hydrogens has been replaced bythe same or different substituents selected from the group consisting ofhalo, lower alkyl, halo-lower alkyl, nitro, amino, lower alkylaclamino,hydroxy, lower alkoxy, phenyl-lower alkoxy, lower alkyl acyloxy, cyano,halo-lower alkoxy and lower alkyl sulfonyl; and the non-toxicpharmaceutically acceptable salts thereof.
 8. A compound according toclaim 7 wherein X is oxygen.
 9. A compound according to claim 8 whereineach of R₆, R₇ and R₈ is hydrogen; and the non-toxic pharmaceuticallyacceptable salts thereof.
 10. A compound according to claim 9 wherein R₃is hydrogen; and the non-toxic pharmaceutically acceptable saltsthereof.
 11. A compound according to claim 10 wherein each of R₅ and R₉is halo, lower alkyl, lower alkoxy, or halo-lower alkyl; and thenon-toxic pharmaceutically acceptable salts thereof.
 12. A compoundaccording to claim 11 wherein each of R₅ and R₉ is lower alkyl; and thenon-toxic pharmaceutically acceptable salts thereof.
 13. A compound ofthe formula ##STR287## wherein: X is oxygen or sulfur;R₂ is hydrogen orlower alkyl; R₃ and R₄ are each independently selected from the groupconsisting of hydrogen, hydroxyl, lower alkanoyl, lower alkyl,cycloloweralkyl, lower alkenyl, lower alkynyl, halo-lower alkyl, loweralkoxy-lower alkyl, hydroxy lower alkyl, phenoxy lower alkyl,diloweralkylamino, aryl, aryl lower alkyl, lower alkoxy, phenoxy, and 5or 6 membered heterocycles selected from the group consisting ofpyridyl, pyrimidyl, pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl,thiazolyl, piperidyl, and morpholinyl, or R₃ and R₄ together with thenitrogen to which they are attached form a 3 to 7 membered ring selectedfrom the group consisting of oxazolidinyl, thiazolidinyl, pyrazolidinyl,imidazolidinyl, piperidyl, piperazinyl, thiamorpholinyl,trimethylenetriaminyl, ethyleneiminyl, and morpholinyl; R₅ and R₉ areeach independently hydrogen, lower alkyl, halo, halo lower alkyl,hydroxy, or lower alkoxy; R₆, R₇ and R₈ are each hydrogen;and, wherein:aryl means phenyl or phenyl in which one or more of the phenyl hydrogenshas been replaced by the same or different substituents selected fromthe group consisting of halo, lower alkyl, halo-lower alkyl, nitro,amino, lower alkylacylamino, hydroxy, lower alkoxy, phenyl-lower alkoxy,lower alkylacyloxy, cyano, halo-lower alkoxy, and lower alkyl sulfonyl;and the non-toxic pharmaceutically acceptable salts thereof.
 14. Acompound according to claim 13 wherein R₅ and R₉ are each halo; and thenon-toxic pharmaceutically acceptable salts thereof.
 15. A compoundaccording to claim 13 wherein R₃ is hydrogen; and the non-toxicpharmaceutically acceptable salts thereof.
 16. A compound according toclaim 15 wherein R₂ is hydrogen and R₄ is hydrogen lower alkyl, hydroxylor lower alkoxy; and the non-toxic pharmaceutically acceptable saltsthereof.
 17. A compound according to claim 16 wherein R₅ and R₉ are eachindependently lower alkyl, lower alkoxy, halo or halo-lower alkyl; andthe non-toxic pharmaceutically acceptable salts thereof.
 18. A compoundof the formula ##STR288## wherein: R₂ is hydrogen or lower alkyl;R₃ andR₄ are each independently selected from the group consisting ofhydrogen, hydroxyl, lower alkanoyl, lower alkyl, cycloloweralkyl, loweralkenyl, lower alkynyl, halo-lower alkyl, lower alkoxy-lower alkyl,hydroxy lower alkyl, phenoxy lower alkyl, diloweralkylamino, aryl oraryl lower alkyl, lower alkoxy, and phenoxy, and 5 or 6 memberedheterocycles selected from the group consisting of pyridyl, pyrimidyl,pyrazolyl, imidazolyl, furyl, thienyl, oxazolyl, thiazolyl, piperidyland morpholinyl, or R₃ and R₄ together with the nitrogen to which theyare attached form a 3 to 7 membered ring selected from the groupconsisting of oxazolidinyl, thiazolidinyl, pyrazolidinyl,imidazolidinyl, piperidyl, piperazinyl, thiamorpholinyl,trimethylenetriaminyl, ethyleneiminyl, and morpholinyl; R₆, R₇ and R₈are each independently hydrogen, lower alkyl, hydroxy or lower alkoxy;R₅ and R₉ are each hydrogen, lower alkyl, hydroxy, lower alkoxy, halo,or halo lower alkyl;and, wherein: aryl means phenyl or phenyl in whichone or more of the phenyl hydrogens has been replaced by the same ordifferent substituents selected from the group consisting of halo, loweralkyl, halo-lower alkyl, nitro, amino, lower alkylacylamino, hydroxy,lower alkoxy, phenyl-lower alkoxy, lower alkylacyloxy, cyano, halo-loweralkoxy, and lower alkyl sulfonyl; and the non-toxic pharmaceuticallyacceptable salts thereof.
 19. A compound according to claim 18 whereinR₅ and R₉ are each independently halo; and the non-toxicpharmaceutically acceptable salts thereof.
 20. A compound according toclaim 18 wherein R₃ is hydrogen; and the non-toxic pharmaceuticallyacceptable salts thereof.
 21. A compound according to claim 20 whereinR₂ is hydrogen and R₄ is hydrogen, lower alkyl, hydroxyl or loweralkoxy; and the non-toxic pharmaceutically acceptable salts thereof. 22.A compound according to claim 21 wherein R₅ and R₉ are eachindependently lower alkyl, lower alkoxy, halo, or halo-lower alkyl. 23.A compound of the formula ##STR289## and the non-toxic pharmaceuticallyacceptable salts thereof.
 24. A compound according to claim 23 havingthe formula ##STR290## and the non-toxic pharmaceutically acceptablesalts thereof.
 25. A compound of the formula ##STR291## and thenon-toxic pharmaceutically acceptable salts thereof. 26.1-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one;and the non-toxic pharmaceutically acceptable salts thereof. 27.1-(2',6'-dimethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride. 28.1-(2',6'-diethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-one;and the non-toxic pharmaceutically acceptable salts thereof. 29.1-(2',6'-diethylphenyl)-4-methylamino-1,2-dihydro-1,3,5-triazin-2-onehydrochloride.